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Primary hyperoxaluria (PH) is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis and eventually kidney failure; the subsequent storage of oxalate can cause life-threatening systemic disease. Diagnosis of PH is often delayed or missed owing to its rarity, variable clinical expression and other diagnostic challenges. Management of patients with PH and kidney failure is also extremely challenging. However, in the past few years, several new developments, including new outcome data from patients with infantile oxalosis, from transplanted patients with type 1 PH (PH1) and from patients with the rarer PH types 2 and 3, have emerged. In addition, two promising therapies based on RNA interference have been introduced. These developments warrant an update of existing guidelines on PH, based on new evidence and on a broad consensus. In response to this need, a consensus development core group, comprising (paediatric) nephrologists, (paediatric) urologists, biochemists and geneticists from OxalEurope and the European Rare Kidney Disease Reference Network (ERKNet), formulated and graded statements relating to the management of PH on the basis of existing evidence. Consensus was reached following review of the recommendations by representatives of OxalEurope, ESPN, ERKNet and ERA, resulting in 48 practical statements relating to the diagnosis and management of PH, including consideration of conventional therapy (conservative therapy, dialysis and transplantation), new therapies and recommendations for patient follow-up. Primary hyperoxaluria is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis, kidney failure and life-threatening systemic disease. This Consensus Statement from ERKNet and OxalEurope provides recommendations for the management of primary hyperoxaluria, including consideration of conventional therapies, new therapies and recommendations for patient follow-up. [ABSTRACT FROM AUTHOR]

Few data exist on the prospects in adulthood for children on chronic renal replacement therapy (RRT). This article summarizes the results of a comprehensive Dutch long-term follow-up study performed in 2000 and 2010 of patients with RRT onset at age <15 years between 1972 and 1992. After a median of 25.5 RRT years, patients had stayed 23% of RRT time on dialysis. We observed a 30 times greater mortality risk compared with age-matched peers with cardiovascular disease (CVD) as the main cause of death during 1972-2000 and infections during 2000-10. The observed shift towards infections was associated with more RRT time with a graft and receiving a stricter CVD protective treatment. For patients >40 years of age, motor disabilities affecting routine activities, skin cancer and severe fatigue were the most disabling sequelae. After 30 years of transplantation, 41% of the survivors had developed cancer, a life-threatening form of squamous cell skin carcinoma being most prevalent. Important delays in autonomy development and educational attainment and a relatively high level of unemployment were observed. Transplanted patients reported a good mental and physical quality of life, but the latter tended to decrease over time. A long period of dialysis was associated with all adverse somatic and psychosocial outcomes. Paediatric nephrologists should aim for transplantation at the earliest possible time and focus on autonomy and educational attainment. Nephrologists should focus on strict CVD prevention, adjustment of immunosuppression to the lowest possible dose and surveillance of malignancy-associated viral infections in patients with childhood end-stage renal disease. [ABSTRACT FROM AUTHOR]

Nedosiran is an N-acetyl-D-galactosamine (GalNAc)–conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near‐normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information. [ABSTRACT FROM AUTHOR]

Nedosiran is an N-acetyl-D-galactosamine (GalNAc)–conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near‐normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information. [ABSTRACT FROM AUTHOR]

Primary hyperoxaluria type 1 (PH1) is a rare inborn error of glyoxylate metabolism of autosomal recessive inheritance, leading to progressive systemic oxalate storage (named 'oxalosis') with a high rate of morbidity and mortality, as well as an unacceptable quality of life for most patients. The adverse outcome, however, is partly due to issues that can be overcome. First, the diagnosis of PH is often delayed due to a general lack of knowledge of the disease among physicians. This accounts specifically for patients with pyridoxine sensitive PH, a group that is paradoxically most easy to treat. Second, lack of adherence to a strict conduction of conservative treatment and optimal urological management may enhance an adverse outcome of the disease. Third, specific techniques to establish PH1 and specific therapies are currently often not available in several low-resources countries with a high prevalence of PH. The management of patients with advanced disease is extremely difficult and warrants a tailor-made approach in most cases. Comprehensive programs for education of local physicians, installation of national centers of expertise, European support of low-resources countries for the management of PH patients and intensified international collaboration on the management of current patients, as well as on conduction of clinical studies, may further improve outcome of PH. [ABSTRACT FROM AUTHOR]

Background. Primary hyperoxaluria (PH) is a rare genetic disease, in which high urinary oxalate (Uox) cause recurrent kidney stones and/or progressive nephrocalcinosis, often followed by early end-stage renal disease, as well as extremely high plasma oxalate, systemic oxalosis and premature death. Oxalobacter formigenes, an anaerobic oxalate degrading bacterium, naturally colonizes the colon of most humans. Orally administered O. formigenes (Oxabact) was found to significantly reduce urine and plasma oxalate. We aimed to evaluate its effect and safety in a randomized, double-blind, placebo-controlled multicenter study.Methods. Oral Oxabact was given to PH patients (>5 years old, Uox > 1.0 mmol/1.73m2/day, glomerular filtration rate (GFR) > 50 mL/min) at nine PH referral sites worldwide. Primary endpoint was the change from baseline in Uox (mmol/1.73m2/day) after 24 weeks of treatment (>20% reduction).Results. Of the 43 subjects randomized, 42 patients received either placebo (23 subjects) or Oxabact (19 subjects). The change in Uox was <20% and not different between groups (P = 0.616). Ad hoc analysis was performed in 37 patients compliant with medication and urine processing. Change in Uox was −19% in subjects given Oxabact and −10% in placebo, (P = 0.288), but −21 and −7% with Uox expressed as molar creatinine ratio (Ox:Cr, mmol/mol, P = 0.06). Reduction of Ox:Cr was more obvious for patients with higher baseline values (>160 mmol/mol, Oxabact −28%, placebo −6%; P < 0.082). No serious adverse events were reported.Conclusion. Oxabact was safe and well tolerated. However, as no significant change in Uox was seen, further studies to evaluate the efficacy of Oxabact treatment are needed. [ABSTRACT FROM AUTHOR]

Cardiovascular disease accounts for 40% of all deaths among pediatric patients with end-stage renal disease (ESRD). ESRD has a particularly large influence on the cardiovascular system in children, as indicated by the more than 700-fold increased risk of cardiac death in affected individuals compared with healthy children of the same age. The prevalence of ESRD is low in children, however, and, consequently, few cardiac deaths occur. As a result, prospective follow-up studies of cardiac risk factors in the pediatric setting are lacking. Nevertheless, cross-sectional data on cardiac disease in children with ESRD have started to emerge. Arterial medial calcification is more prominent in children than classic atherosclerotic intimal calcification. Current data suggest that endothelial dysfunction appears early in renal failure in children, and is followed by arterial medial calcification. This calcification causes arterial wall stiffening and subsequently left ventricular hypertrophy. High systolic blood pressure and serum concentrations of intact parathyroid hormone, calcium and phosphate, as well as long-term dialysis, seem to be important risk factors for cardiovascular disease in pediatric patients with ESRD. These features are important targets for preventive intervention. This Review summarizes the currently available data on cardiovascular disease in children with renal failure. [ABSTRACT FROM AUTHOR]

Context Ber’s Comprehensive Integrative Puzzle aims to assess analytical clinical thinking in medical students. We developed a paediatric version, the MATCH test, in which we added two irrelevant options to each question in order to reduce guessing behaviour. We tested its construct validity and studied the development of integrative skills over time. Methods We administered a test (MATCH 1) to subjects from two universities, both with a 6-year medical training course. Subjects included 30 students from university 1 who had completed a paediatric clerkship in Year 4, 23 students from university 2 who had completed a paediatric clerkship in Year 5, 13 students from both universities who had completed an advanced paediatric clerkship in Year 6, 28 paediatric residents and 17 paediatricians. We repeated this procedure using a second test with different domains in a new, comparable group of subjects (MATCH 2). Results Mean MATCH 1 scores for the respective groups were: Year 4 students: 61.2% (standard deviation [SD] 1.3); Year 5 students: 71.3% (SD 1.6); Year 6 students: 76.2% (SD 1.5); paediatric residents: 88.5% (SD 0.7), and paediatricians: 92.2% (SD 1.1) (one-wayanova F = 104.00, P < 0.0001). Students of both universities had comparable scores. MATCH 1 and 2 scores were comparable. Cronbach’s α-values in MATCH 1 and 2 were 0.92 and 0.91, respectively, for all subjects, and 0.82 and 0.87, respectively, for all students. Conclusions Analytical clinical thinking develops over time, independently of the factual content of the course. This implies that shortened medical training programmes could produce less skilled graduates. [ABSTRACT FROM AUTHOR]

Abstract: The Zellweger spectrum disorders (ZSDs) are characterized by a generalized loss of peroxisomal functions caused by deficient peroxisomal assembly. Clinical presentation and survival are heterogeneous. Although most peroxisomal enzymes are unstable in the cytosol of peroxisome-deficient cells of ZSD patients, a few enzymes remain stable among which alanine:glyoxylate aminotransferase (AGT). Its deficiency causes primary hyperoxaluria type 1 (PH1, MIM 259900), an inborn error of glyoxylate metabolism characterized by hyperoxaluria, nephrocalcinosis, and renal insufficiency. Despite the normal level of AGT activity in ZSD patients, hyperoxaluria has been reported in several ZSD patients. We observed the unexpected occurrence of renal stones in a cohort of ZSD patients. This led us to perform a study in this cohort to determine the prevalence of hyperoxaluria in ZSDs and to find clinically relevant clues that correlate with the urinary oxalate load. We reviewed medical charts of 31 Dutch ZSD patients with prolonged survival (>1 year). Urinary oxalate excretion was assessed in 23 and glycolate in 22 patients. Hyperoxaluria was present in 19 (83%), and hyperglycolic aciduria in 14 (64%). Pyridoxine treatment in six patients did not reduce the oxalate excretion as in some PH1 patients. Renal involvement with urolithiasis and nephrocalcinosis was present in five of which one developed end-stage renal disease. The presence of hyperoxaluria, potentially leading to severe renal involvement, was statistically significant correlated with the severity of neurological dysfunction. ZSD patients should be screened by urinalysis for hyperoxaluria and renal ultrasound for nephrocalcinosis in order to take timely measures to prevent renal insufficiency. [Copyright &y& Elsevier]

As in older adults, cardiovascular disease is the most important cause of death in adolescents and young adult patients with end-stage renal disease (ESRD) since childhood. This concerns patients on dialysis as well as transplant patients, despite the fact that a long duration of dialysis during childhood is an extra mortality risk factor. Left ventricular hypertrophy (LVH), aortic valve calcification, and increased arterial stiffness, but not increased arterial intima media thickening, are the most frequently observed alterations in young adult survivors with childhood ESRD. In transplanted patients a concentric LVH as a result of chronic hypertension is mostly observed; in dialysis patients a more asymmetric septal LVH is found as a result of chronic volume overload. These results suggest that in children and young adults with ESRD chronic pressure and volume overload, a high calcium-phosphate product, and chronic inflammation, but not dyslipidemia, play a role in the development of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Clinical implications of mutation analysis in primary hyperoxaluria type 1. Background. Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism with an extensive clinical and genetic heterogeneity. Although over 50 disease-causing mutations have been identified, the relationship between genotype and clinical outcome remains unclear. The aim of this study was to determine this association in order to find clues for improvement of patient care. Methods. AGXT mutation analysis and assessment of biochemical characteristics and clinical outcome were performed on patients from a Dutch PH1 cohort. Results. Thirty-three of a cohort of 57 PH1 patients, identified in The Netherlands over a period of 30 years, were analyzed. Ten different mutations were found. The most common mutations were the Gly170Arg, Phe152Ile, and the 33insC mutations, with an allele frequency of 43%, 19%, and 15%, respectively. Homozygous Gly170Arg and Phe152Ile mutations were associated with pyridoxine responsiveness and a preserved renal function over time when treatment was timely initiated. All patients homozygous for the 33insC mutation had end-stage renal disease (ESRD) before the first year of age. In two unrelated patients, a new Val336Asp mutation was found coupled with the Gly170Arg mutation on the minor allele. We also found 3 patients homozygous for a novel Gly82Arg mutation with adverse outcome in 2 of them. Conclusion. Early detection of Gly170Arg and Phe152Ile mutations in PH1 has important clinical implications because of their association with pyridoxine responsiveness and clinical outcome. The association of a homozygous 33insC mutation with severe infantile ESRD, resulting in early deaths in 2 out of 3 cases, warrants a choice for prenatal diagnostics in affected families. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease is the most important cause of death in patients with pediatric end-stage renal disease (ESRD). Yet, few data exist on cardiac function in these patients. We assessed the extent of cardiac abnormality and analyzed its association with potential determinants in young adult patients with pediatric ESRD in a long-term follow-up study. Methods: All Dutch living adult patients with ESRD onset at age of 0 to 14 years between 1972 and 1992 were invited for echocardiography and blood pressure assessment. Special attention was paid to evidence of left ventricular hypertrophy (LVH), diastolic dysfunction, and aortic valve calcification. We collected data on determinants by review of all medical charts. Results: Of all the 187 living patients, 140 participated in the study. Of those, 110 patients had received a transplant and 30 patients were on dialysis. Mean age was 29.2 (20.7 to 41.8) years. Left ventricular mass index (LVMI) exceeded 150 g/m2 in 47% of all male patients and 120 g/m2 in 39% of all female patients, both consistent with LVH. Diastolic dysfunction, defined as an early over atrial transmitral blood flow velocity (E/A ratio) <1, was found in 18 (13%) patients; 27 (19%) had aortic valve calcification. Multiple regression analysis revealed the following: a high LVMI was associated with a current high blood pressure (beta=0.46, P < 0.001) and male gender (beta=0.21, P=0.009), a low E/A ratio with aging (beta=-0.28, P < 0.001) and a glomerular filtration rate (GFR) <25 mL/min/1.73 m2 (beta=-0.29, P < 0.001), and aortic valve calcification with prolonged peritoneal dialysis (beta=0.36, P < 0.001). Conclusion: Young adult patients with pediatric ESRD are at risk for LVH caused by hypertension and for aortic valve calcification. Diastolic function decreases with age and is enhanced by a current low GFR. Prolonged peritoneal dialysis may enhance aortic valve calcification. [ABSTRACT FROM AUTHOR]

Background: Little is known about the late effects of juvenile end-stage renal disease (ESRD) on bone integrity. To establish clinical manifestations of metabolic bone disease and bone mineral density (BMD) in young adult patients with juvenile ESRD, we performed a long-term outcome study. Methods: A cohort was formed of all Dutch patients with onset of ESRD between 1972 and 1992 at age 0 to 14 years, born before 1979. Data were collected by review of medical charts, current history, physical examination, and performing dual energy x-ray absorptiometry (DEXA) of the lumbar spine and the femoral neck. Results: Clinical information was retrieved in 247 out of 249 patients. Of all of these patients, 61.4% had severe growth retardation (<-2 SD), 36.8% had clinical symptoms of bone disease, and 17.8% were disabled by bone disease. Growth retardation and clinical bone disease were associated with a long duration of dialysis. DEXA was performed in 140 out of 187 living patients. Mean BMD +/- SD corrected for gender and age (Z score) of the lumbar spine was -2.12 +/- 1.4 and of the femoral neck was -1.77 +/- 1.4. A low lean body mass was associated with a low lumbar spine and a low femoral neck BMD; male gender, physical inactivity and aseptic bone necrosis were associated with a low lumbar spine BMD. Conclusion: Bone disease is a major clinical problem in young adults with pediatric ESRD. Further follow-up is needed to establish the impact of the low bone mineral densities found in these patients. [ABSTRACT FROM AUTHOR]

Mortality and causes of death of end-stage renal disease in children: A Dutch cohort study.. Background: To establish mortality rates, causes of death, and determinants of mortality in children with end-stage renal disease (ESRD), we performed a national long-term follow up study. Methods: Mortality rate was determined in all Dutch patients with onset of ESRD at ages 0 to 14 years in the period between 1972 and 1992. Causes of death and mortality determinants were investigated in all patients of this cohort who were born before 1979. Data were derived from the Dutch Registry for patients on renal replacement therapy (RRT), medical charts and National Health Database. Results: Of all 381 patients 85 had died. The overall mortality rate (MR) was 1.57/100 patient-years, and the standardized mortality rate (SMR) was 31.0. The MR for patients 0 to 5 and 6 to 10 years old at onset of ESRD decreased from, respectively, 7.0 (range 0–14.9) to 3.9 (1.2–6.7) and 4.3 (1.1–7.5) to 1.6 (0.3–2.8) between the periods 1972–1981 and 1982–1992. The mortality hazard ratio of relatively long standing dialysis and of long standing hypertension were, respectively, 7.2 (4.4–11.8) and 3.1 (2.1–4.6), of cyclosporine-introduction in transplanted patients 0.3 (0.1–0.4). Overall cerebrovascular accidents (24%) and infections (21%) were the most common causes of death; after 10 years of RRT cardiac death (7/21) was most prevalent. Cardiovascular death was most prominent in dialysis as well as transplanted patients. Conclusion: Survival in children with ESRD has increased over the last 20 years, but the SMR remains high. Early transplantation and a more vigorous approach toward hypertension and infection may be mandatory in order to further reduce mortality. [ABSTRACT FROM AUTHOR]

The clinical presentation of primary hyperoxaluria in children ranges from mildly symptomatic nephrocalcinosis to very early onset end-stage kidney failure with systemic oxalosis, a devastating complication. We review the various manifestations of pediatric hyperoxaluria, treatment options for children with preserved kidney function and appropriate dialysis regimens. Liver or combined liver/kidney transplantation is currently the only definitive treatment for primary hyperoxaluria type 1, but novel RNA interference treatments offer hope for the future. Finally, we address the medical and ethical dilemmas facing pediatricians treating children with hyperoxaluria. [ABSTRACT FROM AUTHOR]

Unlabelled: In this case report we present a 2-year-old girl with the classical signs of the hyponatraemic hypertensive syndrome. She initially presented with a history of behavioural abnormalities and hyponatraemia (126 mmol/l) and her blood pressure was as high as 220/160 mmHg. After admission, somnolence developed. Intravenous anti-hypertensive therapy was started immediately. The hyponatraemia was treated with i.v. sodium supplementation. The cause of this syndrome proved to be fibromuscular dysplasia of the left renal artery. Finally, a left nephrectomy was performed. With this therapy, blood pressure and serum sodium normalised and the girl promptly regained normal consciousness and behaviour.Conclusion: Behavioural abnormalities in the history of a child without any other neurological symptoms might be one of the first signs of hypertensive encephalopathy. In combination with hyponatraemia, these symptoms should alert the physician to consider the hyponatraemic hypertensive syndrome. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Early intervention is vital to prevent cardiovascular disease in homozygous familial hypercholesterolaemia (HoFH). • This consensus statement provides guidance on performing lipoprotein apheresis in children with HoFH. • Using the Delphi method involving 40 international experts, 22 statements were developed. • Statements cover indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with HoFH. • Furthermore, the role of lipoprotein(a) and liver transplantation in children with HoFH is discussed. [ABSTRACT FROM AUTHOR]

The article presents the highlights of the hybrid 53rd Annual Meeting of the European Society for Pediatric Nephrology (ESPN2021) held in Amsterdam, Netherlands in the summer. Topics include medical ethics, pediatric nephrology, and a comparison of interactive hybrid event format and classical meetings. Also cited are the benefits of integrating onsite and online activities in hybrid meetings.

This article discusses the development and validation of a clinical screening algorithm for the diagnosis of primary hyperoxaluria type 1 (PH1) in adult patients undergoing dialysis. PH1 is a rare genetic disorder characterized by excessive production of oxalate, leading to kidney stones and nephrocalcinosis. The algorithm uses five clinical features, including active nephrolithiasis, presence of nephrocalcinosis, previous graft loss, early initiation of dialysis, and family history of chronic kidney disease, to estimate the probability of PH1. The algorithm showed good performance in terms of discrimination and calibration, and it could be easily implemented in dialysis facilities to identify high-risk patients for further investigation. [Extracted from the article]

The article presents answers to questions in a quiz about acute kidney injury in a girl with Crohn's disease.

A letter to the editor is presented in response to the article "AHUS Caused by Complement Dysregulation: New Therapies on the Horizon," by A. M. Waters and C. Licht, which appeared in a previous issue.

Primary hyperoxaluria (PH) patients overproduce oxalate because of rare genetic errors in glyoxylate metabolism. Recurrent urolithiasis and/or progressive nephrocalcinosis are PH hallmarks and can lead to kidney damage, systemic oxalosis and death. Based on previous studies, we hypothesised that treatment with the oxalate-metabolizing bacterium Oxalobacter formigenes would mediate active elimination of oxalate from the plasma to the intestine of PH patients, thereby reducing urinary oxalate excretion (Uox). The efficacy and safety of O. formigenes (Oxabact™ OC3) were evaluated for 24 weeks in a randomised, placebo-controlled, double-blind study. The primary endpoint was reduction in Uox. Secondary endpoints included change in plasma oxalate (Pox) concentration, frequency of stone events, number of responders, and Uox in several subgroups. Additional post hoc analyses were conducted. Thirty-six patients were randomised; two patients withdrew from placebo treatment. Both OC3 and placebo groups demonstrated a decrease in Uox/urinary creatinine ratio, but the difference was not statistically significant. No differences were observed with respect to change in Pox concentration, stone events, responders’ number or safety measures. In patients with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2, Pox increased by 3.25 µmol/L in the placebo group and decreased by −1.7 µmol/L in the OC3 group (p = 0.13). After 24 weeks, eGFR had declined to a greater degree in the placebo than in the OC3 group: −8.00 ± 2.16 versus −2.71 ± 2.50; p = 0.01. OC3 treatment did not reduce urinary oxalate over 24 weeks of treatment compared with placebo in patients with PH. The treatment was well tolerated. [ABSTRACT FROM AUTHOR]

Background: Severe chronic kidney disease (CKD) in children and young adults has shown to be associated with abnormal brain development, which may contribute to neurocognitive impairments. We aimed to investigate risk factors for neurocognitive impairment and investigate the relation with structural brain abnormalities in young severe CKD patients. Methods: This cross-sectional study includes 28 patients with severe CKD (eGFR < 30), aged 8–30 years (median 18.5 years), on different treatment modalities (pre-dialysis [n = 8], dialysis [n = 8], transplanted [n = 12]). We assessed neurocognitive functioning using a comprehensive test battery and brain structure by magnetic resonance imaging metrics of brain volume and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD] measured with diffusion tensor imaging). Multivariate regression and mediation analyses were performed between clinical CKD parameters, brain structure, and neurocognitive outcome. Results: A combination of risk factors (e.g., longer time since kidney transplantation, longer dialysis duration and late CKD onset) was significantly associated with lower intelligence and/or worse processing speed and working memory. Lower FA in a cluster of white matter tracts was associated with lower intelligence and mediated the relation between clinical risk factors and lower intelligence. Conclusions: Young severe CKD patients with a prolonged duration of kidney replacement therapy, either dialysis or transplantation are at particular risk for impairments in intelligence, processing speed, and working memory. Disrupted white matter integrity may importantly contribute to these neurocognitive impairments. Prospective, longitudinal studies are needed to elucidate the mechanisms involved in CKD and treatment that affect white matter integrity and neurocognitive outcome in young patients. [ABSTRACT FROM AUTHOR]

Background Data on comorbidities in children on kidney replacement therapy (KRT) are scarce. Considering their high relevance for prognosis and treatment, this study aims to analyse the prevalence and implications of comorbidities in European children on KRT. Methods We included data from patients <20 years of age when commencing KRT from 2007 to 2017 from 22 European countries within the European Society of Paediatric Nephrology/European Renal Association Registry. Differences between patients with and without comorbidities in access to kidney transplantation (KT) and patient and graft survival were estimated using Cox regression. Results Comorbidities were present in 33% of the 4127 children commencing KRT and the prevalence has steadily increased by 5% annually since 2007. Comorbidities were most frequent in high-income countries (43% versus 24% in low-income countries and 33% in middle-income countries). Patients with comorbidities had a lower access to transplantation {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61–0.74]} and a higher risk of death [aHR 1.79 (95% CI 1.38–2.32)]. The increased mortality was only seen in dialysis patients [aHR 1.60 (95% CI 1.21–2.13)], and not after KT. For both outcomes, the impact of comorbidities was stronger in low-income countries. Graft survival was not affected by the presence of comorbidities [aHR for 5-year graft failure 1.18 (95% CI 0.84–1.65)]. Conclusions Comorbidities have become more frequent in children on KRT and reduce their access to transplantation and survival, especially when remaining on dialysis. KT should be considered as an option in all paediatric KRT patients and efforts should be made to identify modifiable barriers to KT for children with comorbidities. [ABSTRACT FROM AUTHOR]

End-stage renal disease (ESRD) in children is a medically challenging condition. Due to its rarity and special features, methodologically sound collaborative studies are required. In 2007, a new European registry of pediatric renal replacement therapy (RRT), the ESPN/ERA-EDTA Registry, was launched. In recent years, the Registry has provided comprehensive data on incidence, prevalence, patient characteristics, RRT modalities, and mortality in pediatric ESRD, along with relevant insights into cardiovascular risk, anemia, nutrition and growth, transplantation outcomes, and rare diseases. In this review, we describe the study design and structure underlying the ESPN/ERA-EDTA Registry, summarize the major research findings from more than 20 publications, and discuss current limitations and the future challenges to overcome. [ABSTRACT FROM AUTHOR]

Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis. [ABSTRACT FROM AUTHOR]

Early post-transplant recurrence of oxalate nephropathy in a patient with primary hyperoxaluria type 1, despite pretransplant lumasiran therapy. That being said, the B6 sensitivity was difficult to assess in Patients 1 and 3 since PH1 was diagnosed at the time of kidney failure, and in Patient 5, despite maximal B6 therapy at the time of conservative therapy, an important hyperoxaluria remained. Among patients who reach kidney failure, intensive hemodialysis should be performed; however, systemic oxalosis worsens despite intensive dialysis, and bone is the main compartment for oxalate storage. However, the proposed thresholds of POx for a safe transplant procedure, namely around 20 µmol/L [[13]], appear quite optimistic and probably not attainable in most patients, keeping in mind the POx levels observed in dialysis in non-PH1 patients. [Extracted from the article]

Background: Children with chronic kidney disease (CKD) generally have worse educational and psychosocial outcomes compared with their healthy peers. This can impair their ability to manage their treatment, which in turn can have long-term health consequences through to adulthood. We attempted to capture the experiences of children with CKD and to describe the perspectives of their parents and caregivers on access to educational and psychosocial support. Methods: Children with CKD (n = 34) and their caregivers (n = 62) were sampled via focus groups from pediatric hospitals in Australia, Canada, and the USA. Sixteen focus groups were convened and the transcripts were analyzed thematically. Results: We identified four themes: disruption to self-esteem and identity (emotional turmoil of adolescence, wrestling with the sick self, powerlessness to alleviate child's suffering, balancing normality and protection); disadvantaged by lack of empathy and acceptance (alienated by ignorance, bearing the burden alone); a hidden and inaccessible support system (excluded from formal psychological support, falling behind due to being denied special considerations); and building resilience (finding partners in the journey, moving towards acceptance of the illness, re-establishing childhood). Conclusions: Children with CKD and their caregivers encountered many barriers in accessing psychosocial and educational support and felt extremely disempowered and isolated as a consequence. Improved availability and access to psychosocial and educational interventions are needed to improve the wellbeing and educational advancement of children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

Graph: Graphical Abstract Primary hyperoxaluria type 1 (PH1) is an inherited disorder that leads to endogenous overproduction of oxalate and glycolate. In kidney failure, elevated plasma oxalate (Pox) is the most important biomarker for PH1, but Pox may also be elevated in non-PH patients with kidney failure, which complicates its interpretation. Our primary aim was determining Pox and Pgly in non-PH dialysis patients and comparing these results to retrospectively collected data of PH1 patients with kidney failure. [Extracted from the article]

Background: Left ventricular dysfunction is an important co-morbidity of end-stage renal disease (ESRD) and is associated with a poor prognosis in the adult population. In pediatric ESRD, left ventricular function is generally well preserved, but limited information is available on early changes in myocardial function. The aim of this study was to investigate myocardial mechanics in pediatric patients with ESRD using speckle-tracking echocardiography (STE). Methods: Echocardiographic studies, including M-mode, tissue Doppler imaging (TDI) and STE, were performed in 19 children on dialysis, 17 transplant patients and 33 age-matched controls. Strain measurements were performed from the apical four-chamber and the short axis view, respectively. Results: The interventricular and left ventricular posterior wall thickness was significantly increased in dialysis and transplant patients compared to healthy controls. No significant differences were found in shortening fraction, ejection fraction and systolic tissue Doppler velocities. Dialysis and transplant patients had a decreased mean longitudinal strain compared to healthy controls, with a mean difference of 3.1 [95 % confidence interval (CI) 2.0-4.4] and 2.7 (95 % CI 1.2-4.2), respectively. No differences were found for radial and circumferential strain. Conclusions: Speckle-tracking echocardiography may reveal early myocardial dysfunction in the absence of systolic dysfunction measured by conventional ultrasound or TDI in children with ESRD. [ABSTRACT FROM AUTHOR]

Background More than 50% of children with chronic kidney disease (CKD) have uncontrolled hypertension, increasing their long-term risk of cardiovascular disease and progression to kidney failure. Children receiving medications or dialysis may also experience acute blood pressure fluctuations accompanied by debilitating symptoms. We aimed to describe the perspectives of children with CKD and their parental caregivers on blood pressure to inform patient-centered care. Methods Secondary thematic analysis was conducted on qualitative data from the Standardized Outcomes in Nephrology—Children and Adolescents initiative, encompassing 16 focus groups, an international Delphi survey and two consensus workshops. We analyzed responses from children with CKD (ages 8–21 years) and caregivers (of children ages 0–21 years) pertaining to blood pressure. Results Overall, 120 patients and 250 caregivers from 22 countries participated. We identified five themes: invisibility and normalization (reassured by apparent normotension, absence of symptoms and expected links with CKD), confused by ambiguity (hypertension indistinguishable from cardiovascular disease, questioning the need for prophylactic intervention, frustrated by inconsistent messages and struggling with technical skills in measurement), enabling monitoring and maintaining health (gaging well-being and preventing vascular complications), debilitating and constraining daily living (provoking anxiety and agitation, helpless and powerless and limiting life activities) and burden of medications (overwhelmed by the quantity of tablets and distress from unexpected side effects). Conclusions For children with CKD and their caregivers, blood pressure was an important heath indicator, but uncertainty around its implications and treatment hampered management. Providing educational resources to track blood pressure and minimizing symptoms and treatment burden may improve outcomes in children with CKD. [ABSTRACT FROM AUTHOR]

Background. Considerable disparities exist in the provision of paediatric renal replacement therapy (RRT) across Europe. This study aims to determine whether these disparities arise from geographical differences in the occurrence of renal disease, or whether country-level access-to-care factors may be responsible. Methods. Incidence was defined as the number of new patients aged 0-14 years starting RRT per year, between 2007 and 2011, per million children (pmc), and was extracted from the ESPN/ERA-EDTA registry database for 35 European countries. Country- level indicators onmacroeconomics, perinatal care and physical access to treatment were collected through an online survey and from the World Bank database. The estimated effect is presented per 1SD increase for each indicator. Results. The incidence of paediatric RRT in Europewas 5.4 cases pmc. Incidence decreased from Western to Eastern Europe (-1.91 pmc/1321 km, P < 0.0001), and increased from Southern to Northern Europe (0.93 pmc/838 km, P = 0.002). Regional differences in the occurrence of specific renal diseases were marginal. Higher RRT treatment rates were found in wealthier countries (2.47 pmc/€10 378 GDP per capita, P < 0.0001), among those that tend to spend more on healthcare (1.45 pmc/1.7% public health expenditure, P < 0.0001), and among countries where patients pay less out-of-pocket for healthcare (-1.29 pmc/11.7% out-of-pocket health expenditure, P < 0.0001). Country neonatalmortality was inversely related with incidence in the youngest patients (ages 0-4, -1.1 pmc/2.1 deaths per 1000 births, P = 0.10). Countries with a higher incidence had a lower average age at RRT start, which was fully explained by country GDP per capita. Conclusions. Inequalities exist in the provision of paediatric RRT throughout Europe, most of which are explained by differences in country macroeconomics, which limit the provision of treatment particularly in the youngest patients. This poses a challenge for healthcare policy makers in their aim to ensure universal and equal access to high-quality healthcare services across Europe. [ABSTRACT FROM AUTHOR]

Background: The pathophysiology of neurological dysfunction in severe chronic kidney disease (CKD) in children and young adults is largely unknown. We aimed to investigate brain volumes and white matter integrity in this population and explore brain structure under different treatment modalities. Methods: This cross-sectional study includes 24 patients with severe CKD (eGFR < 30) aged 8–30 years (median = 18.5, range = 9.1–30.5) on different therapy modalities (pre-dialysis, n = 7; dialysis, n = 7; transplanted, n = 10) and 21 healthy controls matched for age, sex, and parental educational level. Neuroimaging targeted brain volume using volumetric analysis on T1 scans and white matter integrity with tract-based spatial statistics and voxel-wise regression on diffusion tensor imaging (DTI) data. Results: CKD patients had lower white matter integrity in a widespread cluster of primarily distal white matter tracts compared to healthy controls. Furthermore, CKD patients had smaller volume of the nucleus accumbens relative to healthy controls, while no evidence was found for abnormal volumes of gray and white matter or other subcortical structures. Longer time since successful transplantation was related to lower white matter integrity. Exploratory analyses comparing treatment subgroups suggest lower white matter integrity and smaller volume of the nucleus accumbens in dialysis and transplanted patients relative to healthy controls. Conclusions: Young CKD patients seem at risk for widespread disruption of white matter integrity and to some extent smaller subcortical volume (i.e., nucleus accumbens). Especially patients on dialysis therapy and patients who received a kidney transplant may be at risk for disruption of white matter integrity and smaller volume of the nucleus accumbens. [ABSTRACT FROM AUTHOR]

We present the 6-month primary analysis data from ILLUMINATE-C, a single-arm, phase 3 study to evaluate lumasiran, an RNAi therapeutic which inhibits oxalate production, in patients with PH1 and impaired kidney function. Key inclusion criteria: genetically confirmed PH1 diagnosis, eGFR ≤45 mL/min/1.73 m², plasma oxalate (POx) ≥20 µmol/L (upper limit of normal=12 µmol/L). Cohort A: patients who did not require dialysis or kidney transplantation at study start. Cohort B: patients on hemodialysis. Primary endpoints: percent change in POx from baseline to Month (M) 6 (cohort A); percent change in pre-dialysis POx from baseline to M6 (cohort B). Baseline mean (SD) POx was 64.7 (41.3) µmol/L in cohort A (N=6) and 108.4 (29.5) µmol/L in cohort B (N=15). In cohorts A and B, respectively, lumasiran led to 33.33% (95%CI: -15.16, 81.82) and 42.43% (95%CI: 34.15, 50.71) least-square mean reductions in POx from baseline to M6 (averaged across M3-6). The most common lumasiran-related AEs were injection-site reactions (all mild). Lumasiran resulted in substantial reductions in POx in PH1 patients with CKD 3b-5, with an acceptable safety profile through M6. [ABSTRACT FROM AUTHOR]

A quiz about a case of acute kidney injury in a 15-year-old girl with Crohn's disease is presented.

Background: Evidence-based guidelines for pediatric renal transplantation (Tx) are lacking. This may lead to unwanted treatment variations. We aimed to quantify the variation in treatment policies and its consequences in daily practice in 11 centers that provide renal Tx for children in three European countries. Methods: We surveyed Tx policies in all ten centers in the Netherlands and Belgium and one center in Germany. We compared Tx policies with the therapies actually provided and with recommendations from available published guidelines and existing literature. Information on treatment policies was obtained by a questionnaire; information on care actually provided was registered prospectively from 2007 to 2011. The clinical guidelines were identified by searches of MEDLINE and websites of pediatric nephrology organizations. Results: Between centers, we found discrepancies in policies on: the minimum accepted recipient weight (8-12 kg), the maximum living and deceased donor age (50-75 and 45-60 years, respectively). HLA-match policies varied between acceptation of all mismatches to at least 1A1B1DR match donor transplantations amounting to 49 % in the Netherlands versus 26 % in Belgium ( p = 0.006). Conclusions: Management policies for renal Tx in children vary considerably between centers and nations. This has a direct impact on the delivered care, and by extrapolation, on health outcome. [ABSTRACT FROM AUTHOR]

Patients with atypical haemolytic uremic syndrome (aHUS) with a mutation in the gene encoding membrane cofactor protein ( CD46) are known to have a better prognosis than those with mutations in factor H ( CFH) or factor I ( CFI), but a small number of the former still proceed to end-stage renal failure. Plasma therapy (PE) is the recommended approach to treat both acute episodes and prevent recurrences in aHUS, but studies have yet to show PE efficacy in aHUS associated with a CD46 mutation. The factors determining failure to treatment are not clear and may be related to the mutation involved or to insufficient treatment. Our experience of PE in a family of three sisters with CFH-associated aHUS suggests that intensive and prophylactic PE allows renal function to be maintained in both native kidneys and allografts. The success of this strategy has led us to use it in all cases of aHUS. Here, we describe the effect of this strategy in a child with aHUS and a CD46 mutation. The initial episode was treated with daily PE, resulting in the recovery of renal function. However, over the next 4 years, there was a progressive decline in renal function to end-stage renal failure, with evidence of an on-going thrombotic microangiopathy despite continuous prophylactic PE. Prophylactic PE does not influence the natural course of aHUS and CD46 mutation. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (HUS) frequently leads to end-stage renal failure and can relapse after transplantation. A 12-year-old girl presenting with familial atypical HUS with a factor H mutation was successfully transplanted 6 years after a first transplant that had failed because of immediate recurrent HUS. Prophylactic plasma exchange before and after transplantation was used. Two months after transplantation, concomitant with a reduction in plasma exchange frequency, the plasma creatinine increased from 70 µmol/l to 194 µmol/l in 2 weeks without thrombocytopenia or signs of hemolytic anemia. The patient had minimal clinical symptoms and a presumptive diagnosis of graft rejection was made. Despite treatment with six daily pulses of methylprednisolone, plasma creatinine continued to increase and a graft biopsy was therefore undertaken. This showed the typical appearance of a thrombotic microangiopathy without any evidence of rejection. Despite daily plasmapheresis and replacement of cyclosporine with tacrolimus, there was no improvement and transplant nephrectomy was undertaken. This patient demonstrates that HUS can recur in a kidney transplant without the diagnostic hematological features and emphasizes the need for early transplant biopsy in such patients showing a decline in transplant function. [ABSTRACT FROM AUTHOR]

Background: Primary hyperoxaluria type 1 (PH1) is characterized by hepatic overproduction of oxalate and often results in kidney failure. Liver-kidney transplantation is recommended, either combined (CLKT) or sequentially performed (SLKT). The merits of SLKT and the place of an isolated kidney transplant (KT) in selected patients are unsettled. We systematically reviewed the literature focusing on patient and graft survival rates in relation to the chosen transplant strategy. Methods: We searched MEDLINE and Embase using a broad search string, consisting of the terms 'transplantation' and 'hyperoxaluria'. Studies reporting on at least four transplanted patients were selected for quality assessment and data extraction. Results: We found 51 observational studies from 1975 to 2020, covering 756 CLKT, 405 KT and 89 SLKT, and 51 pre-emptive liver transplantations (PLT). Meta-analysis was impossible due to reported survival probabilities with varying follow-up. Two individual high-quality studies showed an evident kidney graft survival advantage for CLKT versus KT (87% vs. 14% at 15 years, p<0.05) with adjusted HR for graft failure of 0.14 (95% confidence interval: 0.05–0.41), while patient survival was similar. Three other high-quality studies reported 5-year kidney graft survival rates of 48–89% for CLKT and 14–45% for KT. PLT and SLKT yielded 1-year patient and graft survival rates up to 100% in small cohorts. Conclusions: Our study suggests that CLKT leads to superior kidney graft survival compared to KT. However, evidence for merits of SLKT or for KT in pyridoxine-responsive patients was scarce, which warrants further studies, ideally using data from a large international registry. [ABSTRACT FROM AUTHOR]

Both plasma low-density lipoprotein (LDL) cholesterol levels and risk for premature cardiovascular disease are extremely elevated in patients with homozygous familial hypercholesterolemia (HoFH), despite the use of multiple cholesterol lowering treatments. Given its inborn nature, atherosclerotic plaques are commonly observed in young HoFH patients. Whether intensive lipid lowering strategies result in plaque regression in adolescent patients is unknown. Two HoFH patients with null/null LDLR variants, who participated in the R1500-CL-1629 randomized clinical trial (NCT03399786) evaluating the LDL cholesterol lowering effect of evinacumab (a human antibody directed against ANGPTL3; 15 mg/kg intravenously once monthly), were included in this study. Patients underwent coronary computed tomography angiography (CCTA) before randomization and after 6 months of treatment. Both patient A (aged 12) and B (aged 16) were treated with a statin, ezetimibe and weekly apheresis. Evinacumab decreased mean pre-apheresis LDL cholesterol levels from 5.51 ± 0.75 and 5.07 ± 1.45 mmol/l to 2.48 ± 0.31 and 2.20 ± 0.13 mmol/l and post-apheresis LDL levels from 1.45 ± 0.26 and 1.37 ± 39 mmol/l to 0.80 ± 0.16 and 0.78 ± 0.13 mmol/l in patient A and B, respectively. Total plaque volumes were reduced by 76% and 85% after 6 months of evinacumab treatment in patient A and B, respectively. We describe two severely affected young HoFH patients in whom profound plaque reduction was observed with CCTA after intensive lipid lowering therapy with statins, ezetimibe, LDL apheresis, and evinacumab. This shows that atherosclerotic plaques possess the ability to regress at young age, even in HoFH patients. [Display omitted] • Homozygous familial hypercholesterolemia (HoFH) is characterized by the presence of coronary plaques at a young age. • Two adolescent HoFH patients with profound plaques received aggressive low-density lipoprotein (LDL) lowering. • Profound coronary plaque regression was observed on CCTA imaging. • Atherosclerotic plaques possess the ability to regress at young age, even in HoFH. [ABSTRACT FROM AUTHOR]

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase.Methods: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6.Results: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients.Conclusions: Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.). [ABSTRACT FROM AUTHOR]

Mineral and bone disorder (MBD) is widely prevalent in children with chronic kidney disease (CKD) and is associated with significant morbidity. CKD may cause disturbances in bone remodelling/modelling, which are more pronounced in the growing skeleton, manifesting as short stature, bone pain and deformities, fractures, slipped epiphyses and ectopic calcifications. Although assessment of bone health is a key element in the clinical care of children with CKD, it remains a major challenge for physicians. On the one hand, bone biopsy with histomorphometry is the gold standard for assessing bone health, but it is expensive, invasive and requires expertise in the interpretation of bone histology. On the other hand, currently available non-invasive measures, including dual-energy X-ray absorptiometry and biomarkers of bone formation/resorption, are affected by growth and pubertal status and have limited sensitivity and specificity in predicting changes in bone turnover and mineralization. In the absence of high-quality evidence, there are wide variations in clinical practice in the diagnosis and management of CKD-MBD in childhood. We present clinical practice points (CPPs) on the assessment of bone disease in children with CKD Stages 2–5 and on dialysis based on the best available evidence and consensus of experts from the CKD-MBD and Dialysis working groups of the European Society for Paediatric Nephrology and the CKD-MBD working group of the European Renal Association–European Dialysis and Transplant Association. These CPPs should be carefully considered by treating physicians and adapted to individual patients' needs as appropriate. Further areas for research are suggested. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the case of a 17-year-old female diagnosed with atypical hemolytic uremic syndrome and cerebral artery stenosis associated with complement dysregulation.

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. 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. 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. 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. Image 1 • Lipoprotein apheresis (LA) is safe in children with hoFH with a paucity of side effects. • LA leads to an important reduction of LDL-C and xanthomas in children with hoFH. • Only a small number of children with hoFH reach treatment goals on LA. • There are important differences in LA conduction strategies between different sites. [ABSTRACT FROM AUTHOR]

Secondary hyperparathyroidism (SHPT) is an important complication of advanced chronic kidney disease (CKD) in children, which is often difficult to treat with conventional therapy. The calcimimetic cinacalcet is an allosteric modulator of the calcium-sensing receptor. It has proven to be effective and safe in adults to suppress parathyroid hormone (PTH), but data on its use in children are limited. To date, studies in children only consist of two randomized controlled trials, nine uncontrolled interventional or observational studies, and case reports that report the efficacy of cinacalcet as a PTH-lowering compound. In 2017, the European Medical Agency approved the use of cinacalcet for the treatment of SHPT in children on dialysis in whom SHPT is not adequately controlled with standard therapy. Since evidence-based guidelines are so far lacking, we present a position statement on the use of cinacalcet in paediatric dialysis patients based on the available evidence and opinion of experts from the European Society for Paediatric Nephrology, Chronic Kidney Disease-Mineral and Bone Disorder and Dialysis Working Groups, and the ERA-EDTA. Given the limited available evidence the strength of these statements are weak to moderate, and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. Audit and research recommendations to study key outcome measures in paediatric dialysis patients receiving cinacalcet are suggested. [ABSTRACT FROM AUTHOR]

Background There is no consensus regarding the timing of dialysis therapy initiation for end-stage kidney disease (ESKD) in children. As studies investigating the association between timing of dialysis initiation and clinical outcomes are lacking, we aimed to study this relationship in a cohort of European children who started maintenance dialysis treatment. Methods We used data on 2963 children from 21 different countries included in the European Society of Pediatric Nephrology/European Renal Association–European Dialysis and Transplant Association Registry who started renal replacement therapy before 18 years of age between 2000 and 2014. We compared two groups according to the estimated glomerular filtration rate (eGFR) at start: eGFR ≥8 mL/min/1.73 m2 (early starters) and eGFR <8 mL/min/1.73 m2 (late starters). The primary outcomes were patient survival and access to transplantation. Secondary outcomes were growth and cardiovascular risk factors. Sensitivity analyses were performed to account for selection- and lead time-bias. Results The median eGFR at the start of dialysis was 6.1 for late versus 10.5 mL/min/1.73 m2 for early starters. Early starters were older [median: 11.0, interquartile range (IQR): 5.7–14.5 versus 9.4, IQR: 2.6–14.1 years]. There were no differences observed between the two groups in mortality and access to transplantation at 1, 2 and 5 years of follow-up. One-year evolution of height standard deviation scores was similar among the groups, whereas hypertension was more prevalent among late initiators. Sensitivity analyses resulted in similar findings. Conclusions We found no evidence for a clinically relevant benefit of early start of dialysis in children with ESKD. Presence of cardiovascular risk factors, such as high blood pressure, should be taken into account when deciding to initiate or postpone dialysis in children with ESKD, as this affects the survival. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficacy of statin therapy in children is well established, but longer follow-up studies evaluating changes in the risk of cardiovascular disease are scarce.Methods: We report a 20-year follow-up study of statin therapy in children. A total of 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima-media thickness. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents.Results: Of the original cohort, 184 of 214 patients with familial hypercholesterolemia (86%) and 77 of 95 siblings (81%) were seen in follow-up; among the 214 patients, data on cardiovascular events and on death from cardiovascular causes were available for 203 (95%) and 214 (100%), respectively. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter (from 6.13 to 4.16 mmol per liter) - a decrease of 32% from the baseline level; treatment goals (LDL cholesterol <100 mg per deciliter [2.59 mmol per liter]) were achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in siblings (mean difference adjusted for sex, -0.0001 mm per year; 95% confidence interval, -0.0010 to 0.0008). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs. 26% and 0% vs. 7%, respectively).Conclusions: In this study, initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood. (Funded by the AMC Foundation.). [ABSTRACT FROM AUTHOR]

Homozygous familial hypercholesterolemia (hoFH) is a rare genetic disease, hallmarked by a lifelong exposure to very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated, patients can experience a cardiovascular event in the first decade of life. Early detection and monitoring of subclinical atherosclerosis in these patients is therefore extremely important. We set out to assess the diagnostic yield of low-dose coronary computed tomography angiography (cCTA) compared to echocardiography in detecting subclinical atherosclerosis. For this single-center cross-sectional study, we included all pediatric hoFH patients treated with lipoprotein-apheresis (LA) in Amsterdam UMC. We performed both cCTA and echocardiography in all patients as part of routine follow-up. Six hoFH patients were included. Median ages at diagnosis, onset of LA and cardiovascular assessment (cCTA and echocardiography) were 2.6, 6.5, 10.8 and 11.1 years, respectively. Echocardiography revealed no signs of atherosclerosis in any of the six patients. In two patients, mild dilatation of the cardiac chambers was detected and two patients showed signs of mitral or aortic insufficiency. On cCTA, however, non-calcified plaques without stenosis were detected in four patients. In two patients calcified coronary plaques were found at the ostia of the right coronary artery or the left main coronary artery. Aortic root calcifications were found in two patients. Our findings suggest that in hoFH children, low-dose cCTA is superior to echocardiography for the detection of subclinical coronary and aortic root atherosclerosis and should therefore be considered in the routine cardiovascular monitoring of these high-risk children. Image 1 • Low-dose computed tomography angiography (cCTA) enables early detection of subclinical atherosclerosis in homozygous familial hypercholesterolemia (hoFH). • Low-dose cCTA seems superior to echocardiography in assessing atherosclerosis. • Adjusting therapy on atherosclerosis detection might impact outcome in hoFH children. • Low-dose cCTA should be routinely performed in hoFH children. [ABSTRACT FROM AUTHOR]