Background Acute kidney injury (AKI) has been characterized in high-risk pediatric hospital inpatients, in whom AKI is frequent and associated with increased mortality, morbidity, and length of stay. ...The incidence of AKI among patients not requiring intensive care is unknown. Study Design Retrospective cohort study. Setting & Participants 13,914 noncritical admissions during 2011 and 2012 at our tertiary referral pediatric hospital were evaluated. Patients younger than 28 days or older than 21 years of age or with chronic kidney disease (CKD) were excluded. Admissions with 2 or more serum creatinine measurements were evaluated. Factors Demographic features, laboratory measurements, medication exposures, and length of stay. Outcome AKI defined as increased serum creatinine level in accordance with KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Based on time of admission, time interval requirements were met in 97% of cases, but KDIGO time window criteria were not strictly enforced to allow implementation using clinically obtained data. Results 2 or more creatinine measurements (one baseline before or during admission and a second during admission) in 2,374 of 13,914 (17%) patients allowed for AKI evaluation. A serum creatinine difference ≥0.3 mg/dL or ≥1.5 times baseline was seen in 722 of 2,374 (30%) patients. A minimum of 5% of all noncritical inpatients without CKD in pediatric wards have an episode of AKI during routine hospital admission. Limitations Urine output, glomerular filtration rate, and time interval criteria for AKI were not applied secondary to study design and available data. The evaluated cohort was restricted to patients with 2 or more clinically obtained serum creatinine measurements, and baseline creatinine level may have been measured after the AKI episode. Conclusions AKI occurs in at least 5% of all noncritically ill hospitalized children, adolescents, and young adults without known CKD. Physicians should increase their awareness of AKI and improve surveillance strategies with serum creatinine measurements in this population so that exacerbating factors such as nephrotoxic medication exposures may be modified as indicated.
Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating ...parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.
Summary Background Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early ...death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. Methods In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80–320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. Findings Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. Interpretation cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. Funding German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.
Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and ...is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b-5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.
Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach that aggregates ...phenotypes on the basis of patterns described by Mendelian diseases. We mapped the clinical features of 1204 Mendelian diseases into phenotypes captured from the electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In an initial validation, PheRS distinguished cases and controls of five Mendelian diseases. Applying PheRS to 21,701 genotyped individuals uncovered 18 associations between rare variants and phenotypes consistent with Mendelian diseases. In 16 patients, the rare genetic variants were associated with severe outcomes such as organ transplants. PheRS can augment rare-variant interpretation and may identify subsets of patients with distinct genetic causes for common diseases.
In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference ...therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1.
This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics.
Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal.
Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels.
Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
Background
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated ...efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018–004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here.
Methods
Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7–20.5) months).
Results
Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)).
Conclusions
Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of
(expected ~1 in 30 million outbred people).
(glycolate oxidase) silencing is the ...mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong
knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.
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.
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.
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.
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.).
Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants ...and young children with PH1.
This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate.
All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions.
Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.
Display omitted
PDF
