Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.

RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2.

Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs -1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.

Corrigendum: PCRRT Expert Committee ICONIC position paper on prescribing kidney replacement therapy in critically sick children with acute liver failure.

[This corrects the article DOI: 10.3389/fped.2021.833205.].

PCRRT Expert Committee ICONIC Position Paper on Prescribing Kidney Replacement Therapy in Critically Sick Children With Acute Liver Failure.

Management of acute liver failure (ALF) and acute on chronic liver failure (ACLF) in the pediatric population can be challenging. Kidney manifestations of liver failure, such as hepatorenal syndrome (HRS) and acute kidney injury (AKI), are increasingly prevalent and may portend a poor prognosis. The overall incidence of AKI in children with ALF has not been well-established, partially due to the difficulty of precisely estimating kidney function in these patients. The true incidence of AKI in pediatric patients may still be underestimated due to decreased creatinine production in patients with advanced liver dysfunction and those with critical conditions including shock and cardiovascular compromise with poor kidney perfusion. Current treatment for kidney dysfunction secondary to liver failure include conservative management, intravenous fluids, and kidney replacement therapy (KRT). Despite the paucity of evidence-based recommendations concerning the application of KRT in children with kidney dysfunction in the setting of ALF, expert clinical opinions have been evaluated regarding the optimal modalities and timing of KRT, dialysis/replacement solutions, blood and dialysate flow rates and dialysis dose, and anticoagulation methods.

Pediatric Continuous Renal Replacement Therapy (PCRRT) expert committee recommendation on prescribing prolonged intermittent renal replacement therapy (PIRRT) in critically ill children.

INTRODUCTION: Recently, prolonged intermittent renal replacement therapies (PIRRT) have emerged as cost-effective alternatives to conventional CRRT and their use in the pediatric population has started to become more prominent. However, there is a lack of consensus guidelines on the use of PIRRT in pediatric patients in an intensive care setting. METHODS: A literature search was performed on PubMed/Medline, Embase, and Google Scholar in conjunction with medical librarians from both India and the Cleveland Clinic hospital system to find relevant articles. The Pediatric Continuous Renal Replacement Therapy workgroup analyzed all articles for relevancy, proposed recommendations, and graded each recommendation for their strength of evidence. RESULTS: Of the 60 studies eligible for review, the workgroup considered data from 37 studies to formulate guidelines for the use of PIRRT in children. The guidelines focused on the definition, indications, machines, and prescription of PIRRT. CONCLUSION: Although the literature on the use of PIRRT in children is limited, the current studies give credence to their benefits and these expert recommendations are a valuable first step in the continued study of PIRRT in the pediatric population.

Same Donor Laparoscopic Liver and Kidney Procurement for Sequential Living Donor Liver-Kidney Transplantation in Primary Hyperoxaluria Type I.

Background: Sequential liver-kidney transplantation (SeqLKT) from the same living donor has shown excellent results in children with primary hyperoxaluria type 1 (PH1), yet its experience is limited due to the invasiveness of two major procedures for liver-kidney procurement in a single donor. Despite laparoscopic nephrectomy and hepatic left lateral sectionectomy (LLS) being considered standard procedures in living donation, the sequential use of the two laparoscopic approaches in the same living donor has never been reported. Methods: Herein, we present the first two case series of laparoscopic liver-kidney procurement in the same living donor for SeqLKT in children with PH1 and review of the current literature on this topic. Results: In the first case, a 15-month-old boy received a SeqLKT from his 32-year-old mother, who underwent a laparoscopic LLS and, after 8 months, a laparoscopic left nephrectomy. In the second case, a 34-month-old boy received a SeqLKT from his 40-year-old father who underwent laparoscopic LLS followed by hand-assisted right nephrectomy after 4 months. Both donors had uneventful postoperative courses and were discharged within 5 days from each surgery. The first recipient had no complication; the second child after liver transplantation developed a partial thrombosis of the inferior vena cava, which did not preclude the sequential kidney transplantation. After 12 months, donors and recipients displayed normal liver and renal functions. Conclusions: Sequential laparoscopic liver-kidney procurement in the same living donor is safe and feasible, and might be considered as a possible strategy to promote SeqLKT in children with PH1 from the same living donor.

Social Networks and Mobile Applications Use in Young Patients With Kidney Disease.

Objective: To evaluate the use and benefits of social networking sites (SNS) and mobile applications (MA) in young patients with kidney disease (KD). Background: Pediatric KD is prevalent. The Internet is increasingly being used to communicate rapid healthcare information to children about acute and chronic diseases with greater medical care satisfaction. There is a lack of data on social media (SM) utility in pediatric KD. Materials and Methods: A descriptive, observational, and cross-sectional study was conducted on a national level. Data were collected from 4 different centers through a reviewed questionnaire. Results: 83.9% of the 428 participants were Lebanese. The average age was 11.4 years (±7.1). 69.9% had chronic KD out of which 17.4% had undergone a kidney transplant while 9% were on dialysis. 69.6% of the participants affirmed the need of SM for the health of the sick child while only 9.8% are participating in a scientific forum and 4.7% used SM to find a potential organ donor. Some study variables were statistically associated with the participants' age, nationality, and stage of KD. Conclusions: SM is important for the support and management of pediatric KD. We believe that SNS and MA will play a leading role in the lives of our patients in the upcoming future and will push the physician to be an active participant in the evolution of communication networks. To identify the efficacy of SM in enhancing communication between patients and health professionals, further stratified studies are needed.

The added value of WES reanalysis in the field of genetic diagnosis: lessons learned from 200 exomes in the Lebanese population.

BACKGROUND: The past few decades have witnessed a tremendous development in the field of genetics. The implementation of next generation sequencing (NGS) technologies revolutionized the field of molecular biology and made the genetic information accessible at a large scale. However, connecting a rare genetic variation to a complex phenotype remains challenging. Indeed, identifying the cause of a genetic disease requires a multidisciplinary approach, starting with the establishment of a clear phenotype with a detailed family history and ending, in some cases, with functional assays that are crucial for the validation of the pathogenicity of a mutation. METHODS: Two hundred Lebanese patients, presenting a wide spectrum of genetic disorders (neurodevelopmental, neuromuscular or metabolic disorders, etc.), sporadic or inherited, dominant or recessive, were referred, over the last three and a half years, to the Medical Genetics Unit (UGM) of Saint Joseph University (USJ). In order to identify the genetic basis of these diseases, Whole Exome Sequencing (WES), followed by a targeted analysis, was performed for each case. In order to improve the genetic diagnostic yield, WES data, generated during the first 2 years of this study, were reanalyzed for all patients who were left undiagnosed at the genetic level. Reanalysis was based on updated bioinformatics tools and novel gene discoveries. RESULTS: Our initial analysis allowed us to identify the specific genetic mutation causing the disease in 49.5% of the cases, in line with other international studies. Repeated WES analysis enabled us to increase the diagnostics yield to 56%. CONCLUSION: The present article reports the detailed results of both analysis and pinpoints the contribution of WES data reanalysis to an efficient genetic diagnosis. Lessons learned from WES reanalysis and interpretation are also shared.

ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS.

Hereditary defects of coenzyme Q10 biosynthesis cause steroid-resistant nephrotic syndrome (SRNS) as part of multiorgan involvement but may also contribute to isolated SRNS. Here, we report 26 patients from 12 families with recessive mutations in ADCK4. Mutation detection rate was 1.9% among 534 consecutively screened cases. Patients with ADCK4 mutations showed a largely renal-limited phenotype, with three subjects exhibiting occasional seizures, one subject exhibiting mild mental retardation, and one subject exhibiting retinitis pigmentosa. ADCK4 nephropathy presented during adolescence (median age, 14.1 years) with nephrotic-range proteinuria in 44% of patients and advanced CKD in 46% of patients at time of diagnosis. Renal biopsy specimens uniformly showed FSGS. Whereas 47% and 36% of patients with mutations in WT1 and NPHS2, respectively, progressed to ESRD before 10 years of age, ESRD occurred almost exclusively in the second decade of life in ADCK4 nephropathy. However, CKD progressed much faster during adolescence in ADCK4 than in WT1 and NPHS2 nephropathy, resulting in similar cumulative ESRD rates (>85% for each disorder) in the third decade of life. In conclusion, ADCK4-related glomerulopathy is an important novel differential diagnosis in adolescents with SRNS/FSGS and/or CKD of unknown origin.

[Kidney transplantation in pediatric patients: 18-year experience at Hôtel-Dieu de France]. / LA TRANSPLANTATION RÉNALE CHEZ L'ENFANT Dix-huit ans d'expérience à l'Hôtel-Dieu de France.

INTRODUCTION: During the period from September 1993 to March 2011, 79 kidney transplants in children and adolescents less than 18 years old were performed in our department; fifty-six in the familial group and 13 in the cadaveric group. We report in this study: immunosuppression protocols, medical and surgical complications (including rejection episodes), graft and patient survival. MATERIAL AND METHODS: Immunosuppression protocol has been modified throughout those eighteen years. Induction therapy includes serum anti- lymphocyte + cyclosporine + azathioprine and prednisone. Since 2000, azathioprine was replaced by mycophenolate mofetil and since January 2005 cyclosporine was given as well as tacrolymus according to EBV status. Basiliximab-Simulect® was included in the protocol since 2010. RESULTS: Surgical complications were only two lymphoceles, reversible after surgical drainage in the peritoneum. Medical complications were mainly infections or rejections. Thirty-six episodes of rejection occurred: 7 in the commercial group, 16 in the familial group and 13 in the cadaveric group. At the end of the study, 9 patients returned to dialysis, 5 from the cadaveric group, 2 from the familial group and 2 from the commercial group. CONCLUSION: After eighteen years experience in kidney transplant, we believe that kidney transplant remains the optimal treatment for terminal renal failure even for children weighing less than 10 kg. The follow-up of pediatric patients with kidney transplant revealed different positive effects on growth, regular school attendance and psychomotor development. At the end of the study: 24 are at school, 12 at universities, 5 are attending specialized schools and 9 are active workers.

CYTOMEGALOVIRUS INFECTION POST KIDNEY TRANSPLANT: What Should We Know Now?

Cytomegalovirus (CMV) remains one of the most important pathogen responsible for the morbidity and mortality of transplantation patients. The impact on recipients depends on the form of CMV infection knowing that 10% to 50% develop symptomatic disease while solid organ involvement if presumed (e.g. CMV nephritis) may have deleterious outcome and requires histopathology testing. Treatment with antivirals IV ganciclovir and valganciclovir is managed according to early diagnostic tools with quantitative nucleic acid testing (QNAT) and antigenemia that will indicate the extent of disease and monitor response to treatment. CMV prevention in particular conditions of high risk patients has proven to be beneficial, resistance to antivirals and CMV vaccines along with novel therapies are thoroughly discussed in this review describing the new perspectives of CMV infection management.

DONOR SPECIFIC ANTI-HLA ANTIBODIES DETECTION AND IMPACT IN KIDNEY TRANSPLANTATION.

Kidney transplantation is now accepted to be the best treatment for end-stage renal disease. Despite the improvement of immunosuppressive therapy, there is still actually substantial loss of allografts, in part due to uncontrolled humoral immunity. For many years, the primary technique for the detection of anti-HLA antibodies was the CDC (complement dependent cytotoxicity). The recent use of solid phase assays, mainly the Luminex technology allowed detection of antibodies at much lower levels, and it has been shown that these antibodies have negative impact on the graft survival. We herein review the principal techniques for anti-HLA detection and the different presentations of humoral rejection.

[Immunosuppressive protocols in kidney transplantation: with or without induction?]. / PROTOCOLES D'IMMUNOSUPPRESSION EN TRANSPLANTATION RNALE: AVEC OU SANS INDUCTION?

Kidney transplantation is the treatment of choice of end stage kidney disease. Over the years, kidney transplantation progressed tremendously, mainly by the improvement of immunosuppressive drugs used in the prevention of acute rejection. Since the introduction of cyclosporine in the 80s, many immunosuppressive protocols have been established. These protocols are characterized by two strategies: with or without induction. The agents used in induction therapies can be polyclonal or monoclonal antibodies. The decision of using induction therapy relies mainly on the evaluation of the immunological risk in the recipient. Even if protocols with induction have improved early results concerning acute rejection, the protocoles without induction seem justified in some candidates. The optimal immunosuppressive protocol is not yet established, and individualization of immunosuppressive treatment is necessary.

Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome.

We sought to ascertain the long-term outcome and genotype-phenotype correlations available for primary hyperoxaluria type 1 in a large retrospective cohort study. We examined the clinical history of 155 patients (129 families primarily from Western Europe, North Africa, or the Middle East) as well as the enzymatic or genetic diagnosis. The median age at first symptom was 4 years, and at diagnosis 7.7 years, at which time 43% had reached end-stage renal disease. Presentations included: (1) early nephrocalcinosis and infantile renal failure, (2) recurrent urolithiasis and progressive renal failure diagnosed during childhood, (3) late onset with occasional stone passage diagnosed in adulthood, (4) diagnosis occurring on post-transplantation recurrence, and (5) family screening. The cumulative patient survival was 95, 86, and 74% at ages 10, 30, and 50 years, respectively, with the cumulative renal survival of 81, 59, 41, and 10% at ages 10, 20, 30, and 50 years, respectively; 72 patients had undergone a total of 97 transplantations. Among the 136 patients with DNA analysis, the most common mutation was p.Gly170Arg (allelic frequency 21.5%), with a median age at end-stage renal disease of 47 years for homozygotes, 35 years for heterozygotes, and 21 years for other mutations. Our results underscore the severe prognosis of primary hyperoxaluria type 1 and the necessity for early diagnosis and treatment, as well as confirm a better prognosis of the p.Gly170Arg mutation.

[Cardiogenic shock revealing heart disease in infancy and childhood: a Lebanese multicentric study]. / Choc cardiogénique révélant une cardiopathie à l'âge pédiatrique Etude multicentrique libanaise.

OBJECTIVES: Diagnosis, initial workup and immediate prognosis in congenital or acquired heart diseases revealed by cardiogenic shock (CS) in a Lebanese paediatric multicentric study. MATERIAL AND METHODS: During a six-year period (1st January 1999 to 31 December 2004), 56 paediatric patients aged between 0 and 7 years have been admitted to the emergency departments or neonatal and intensive care units in ten different Lebanese hospitals, for high degree of CS suspicion with underlying cardiac disease. All diagnoses were confirmed by echocardiography. RESULTS: All children were initially in a critical condition with signs of CS. Congenital heart diseases (CHD), specially left obstructive diseases (coarctation of the aorta, critical aortic stenosis, hypoplastic left heart syndrome) were the main etiologies found in newborns, followed by dilated cardiomyopathies in infants and children. Mortality was higher in the following two groups of patients: intubation, no diuresis after the first hour of admission despite therapeutic measures (prostaglandines in newborns, dopamine, dobutamine and furosemide). Beside those pathologies necessitating specific treatment, all the CHD (excluding hypoplastic left heart syndrome, one case of critical aortic coarctation and one case of congenital mitral regurgitation) were transferred to the catheterization laboratory or to surgery in a good hemodynamic condition. CONCLUSION: CS remains a notable medical problem observed in the emergency and paediatric intensive care units in Lebanon. Immediate prognosis is related to: immediate recognition of the CS, nature of the cardiopathy and initial response to therapeutic procedures such as rapid improvement of respiratory status and rapid diuresis. Echocardiography is a reliable, quick and non-invasive procedure for initial diagnosis.

Salmonella typhi in a child with urinary tract infection and urolithiasis.

Salmonella species are a rare cause of urinary tract infections in children. They have been associated with a higher incidence of structural abnormalities or immunosuppressive status. We report the case of an 11-year-old girl with urinary tract infection (UTI) secondary to Salmonella typhi and associated with urolithiasis. A review of the subject is then discussed.

[Indications for therapeutic activity of cyclosporine]. / Indications therapeutiques actuelles de la ciclosporine.

Ciclosporine was launched in therapeutic use in 1978. It marked the transplantation era due to the success of organ transplantation. Ciclosporine is actually used in bone marrow transplantation and in the transplantation of slid organs such as kidney, liver, heart, lungs, lung-heart, pancreas and bowel. It was proven also efficient in the treatment of auto-immune diseases especially in the treatment of psoriasis and nephrotic syndrom. Pharmacokinetic and drug interactions of ciclosporine have to be taken in consideration in order to allow an optimal use of the medication. However, the drug presents a long list of side effects: hypertension, increased level of serum creatinine, hypomagnesemia, severe gingivitis, maxillary modification, which can restrict the therapeutic use of the drug.