Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial.

Background And Objectives: 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.

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1.

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).

Simultaneous sequencing of 37 genes identified causative mutations in the majority of children with renal tubulopathies.

The clinical diagnosis of inherited renal tubulopathies can be challenging as they are rare and characterized by significant phenotypic variability. Advances in sequencing technologies facilitate the establishment of a molecular diagnosis. Therefore, we determined the diagnostic yield of a next generation sequencing panel assessing relevant disease genes in children followed through three national networks with a clinical diagnosis of a renal tubulopathy.

Clinical and molecular aspects of distal renal tubular acidosis in children.

Background: Distal renal tubular acidosis (dRTA) is characterized by hyperchloraemic metabolic acidosis, hypokalaemia, hypercalciuria and nephrocalcinosis. It is due to reduced urinary acidification by the α-intercalated cells in the collecting duct and can be caused by mutations in genes that encode subunits of the vacuolar H-ATPase (ATP6V1B1, ATP6V0A4) or the anion exchanger 1 (SLC4A1). Treatment with alkali is the mainstay of therapy.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3.

Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome).

The study of families with rare inherited forms of hypo- and hyper-tension has been one of the most successful strategies to probe the molecular pathophysiology of blood pressure control and has revealed dysregulation of distal nephron Na+ reabsorption to be a common mechanism. FHHt (familial hyperkalaemic hypertension; also known as Gordon's syndrome) is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+-Cl- co-transporter NCC [also known as SLC12A3 (solute carrier family 12 member 3)] and is effectively treated by thiazide diuretics and/or dietary salt restriction. Variation in at least four genes can cause FHHt, including WNK1 [With No lysine (=K) 1] and WNK4, KLHL3 (kelch-like family member 3), and CUL3 (cullin 3).

The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3.

Background: Mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene have been recently identified in patients with atypical primary hyperoxaluria (PH). However, it was not clearly established whether these mutations caused disease via loss of function or activation of the gene product.

Methods: Whole-gene sequencing of HOGA1 was conducted in 28 unrelated patients with a high clinical suspicion of PH and in whom Types 1 and 2 had been excluded.

Cysteamine toxicity in patients with cystinosis.

Objective: To report new adverse effects of cysteamine.

Study Design: Detailed clinical information was obtained from the patients' physicians.

Results: New adverse events were reported in 8 of 550 patients with cystinosis treated with cysteamine in Europe during the last 5 years.

Primary cultures of renal proximal tubule cells derived from individuals with primary hyperoxaluria.

The primary hyperoxalurias, PH1 and PH2, are inherited disorders caused by deficiencies of alanine:glyoxylate aminotransferase and glyoxylate reductase, respectively. Mutations in either of these enzymes leads to endogenous oxalate overproduction primarily in the liver, but most pathological effects are exhibited in the kidney ultimately leading to end-stage renal failure and systemic oxalosis. To provide a non-invasive means of accessing kidney cells from individuals with primary hyperoxaluria, we have derived primary cultures of renal proximal tubule cells from the urine of these patients.

Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes.

Glutathione depletion and increased apoptosis rate in human cystinotic proximal tubular cells.

We have determined levels of glutathione (GSH), ATP, mitochondrial complex activity and apoptosis rate in proximal tubular cells (PTCs) exfoliated from urine in cystinotic (n=9) and control (n=9) children. Intracellular GSH was significantly depleted in cystinotic PTCs compared with controls (6.8 nmol GSH/mg protein vs 11.

Childhood thin GBM disease: review of 22 children with family studies and long-term follow-up.

Thin glomerular basement membrane (GBM) disease is generally known to have a good renal prognosis, although renal insufficiency has sometimes been reported and the overlap with Alport syndrome implies that a good prognosis cannot be guaranteed. In order to shed light on long-term prognosis of thin GBM disease we have retrospectively evaluated 22 children with persistent haematuria and biopsy-proven thin GBM. Mean follow up was 7 years (range 2-17 years), mean age at onset was 7 years (range 1.

Exfoliated human proximal tubular cells: a model of cystinosis and Fanconi syndrome.

The renal Fanconi syndrome (FS) is characterised by generalised proximal tubular dysfunction. Cystinosis is the most common genetic cause of the FS and results from defective function of cystinosin, due to mutations of the CTNS gene leading to intralysosomal cystine accumulation. Despite these advances in our understanding of the molecular basis of cystinosis, the mechanisms of proximal tubular cell (PTC) dysfunction are still unknown.

Aetiological factors in paediatric urolithiasis.

The aetiology of stones in children differs from that in adults. Young children, especially boys, are prone to infective stones, although this type of calculi is decreasing in frequency over time in prosperous countries. Two monogenic causes, cystinuria and hyperoxaluria, each account for 5-15% of paediatric stones.

Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy.

Unlabelled: Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant condition due to heterozygous loss of function calcium sensing receptor (CaSR) mutations. However, individuals who are homozygous for CaSR mutations have neonatal severe hyperparathyroidism (NSHPT), which unlike the relatively benign and asymptomatic FHH can be fatal without parathyroidectomy. We report three patients with NSHPT associated with marked hypercalcaemia and severe hyperparathyroidism with related skeletal demineralisation.

Nephrocalcinosis and medullary cysts in 3-methylglutaconic aciduria.

3-methylglutaconic aciduria is frequently found during urine organic acid analysis and is widely regarded as a marker of a mitochondrial disorder, the clinical features of which are very heterogeneous. We describe two siblings with 3-methylglutaconic aciduria in whom renal ultrasonography showed echogenic medullae consistent with nephrocalcinosis. One patient also developed medullary cysts.

Neonatal nephrocalcinosis in association with glucose-galactose malabsorption.

We report a case of severe nephrocalcinosis related to hypercalcaemia in a newborn with glucose-galactose malabsorption. He presented with poor growth and was noted to have polyuria, which was later recognised to be severe watery diarrhoea. We discuss the possible aetiological factors for nephrocalcinosis in this condition.

Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation.

Background: Familial juvenile hyperuricemic nephropathy (FJHN) is a dominantly inherited condition characterized by young-onset hyperuricemia, gout, and renal disease. The etiologic genes are unknown, although a locus on chromosome 16 has been identified in some kindreds. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with dominant inheritance of a variety of disorders of renal development, particularly renal cystic disease and early onset diabetes; hyperuricemia has been reported in some kindreds.

Immunolocalization of cystinosin, the protein defective in cystinosis.

Cystinosis is an autosomal recessive disorder associated with excessive lysosomal cystine accumulation secondary to defective lysosomal cystine efflux. CTNS, the gene mutated in cystinosis, codes for the lysosomal membrane protein cystinosin. Antisera were raised in rabbits to a carboxy-terminal oligopeptide sequence from cystinosin.

Characterization of renal chloride channel (CLCN5) mutations in Dent's disease.

Dent's disease is an X-linked renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure. The disease is caused by mutations in a renal chloride channel gene, CLCN5, which encodes a 746 amino acid protein (CLC-5), with 12 to 13 transmembrane domains. In this study, an additional six unrelated patients with Dent's disease were identified and investigated for CLCN5 mutations by DNA sequence analysis of the 11 coding exons of CLCN5.