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.).
Childhood obesity is associated with later development of significant renal morbidity. We evaluated the impact of the degree of insulin sensitivity on estimated glomerular filtration rate (eGFR) and ...determined the factors associated with eGFR in obese children. We further tested the relation of eGFR to clinical outcomes such as blood pressure and microalbuminuria.
We evaluated the relation of whole body insulin sensitivity and estimated glomerular filtration rate (eGFR) across the spectrum of obesity in children and adolescents. eGFR was calculated using the iCARE formula, which has been validated in obese children with varying glucose tolerance.
1080 children and adolescents with overweight and obesity (701 females and 379 males) participated. Insulin sensitivity was a strongly negatively associated with (B = -2.72, p < 0.001) eGFR), even after adjustment for potential confounders. Male sex emerged to be significantly associated with eGFR with boys having greater values than girls (B = 18.82, p < 0.001). Age was a positively associated (B = 2.86, p < 0.001) with eGFR. Whole body and hepatic insulin sensitivity decreased across eGFR quartiles. Adjusted eGFR was tightly positively associated with systolic blood pressure (B = 0.09, p = 0.003) and negatively associated with the presence of microalbuminuria (B = -2.18, p = 0.04).
eGFR tends to increase with greater degrees of insulin resistance in children and adolescents representing hyperfiltration and is associated with cardiovascular risk factors. Longitudinal studies are needed to determine the natural history of childhood insulin resistance related hyperfiltration in regards to future kidney disease.
Chronic kidney disease (CKD) constitutes a worldwide epidemic, affecting approximately 10% of the global population, and imposes significant medical, psychological, and financial burdens on society. ...Individuals with CKD often face elevated morbidity and mortality rates, mainly due to premature cardiovascular events. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications, including atherosclerosis, cardiovascular disease (CVD), protein-energy wasting, and the aging process. Over the past two decades, a substantial body of evidence has emerged, identifying chronic inflammation as a central element of the uremic phenotype. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications in dialysis patients, including atherosclerosis, CVD, protein-energy wasting, and the aging process. Remarkably, chronic inflammation also impacts patients with CKD who have not yet required renal replacement therapy. While extensive research has been conducted on the involvement of both the adaptive and innate immune systems in the pathogenesis of CKD-related complications, this wealth of data has not yet yielded well-established, effective treatments to counteract this ongoing pathological process. In the following review, we will examine the established components of the innate immune system known to be activated in CKD and provide an overview of the current therapeutic approaches designed to mitigate CKD-related chronic inflammation.
Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of ...alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of “heterozygosity mapping”—a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline.
We describe two siblings from a consanguineous family with autosomal recessive Fanconi's syndrome and hypophosphatemic rickets. Genetic analysis revealed a homozygous in-frame duplication of 21 bp in ...SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, as the causative mutation. Functional studies in Xenopus laevis oocytes and in opossum kidney cells indicated complete loss of function of the mutant NaPi-IIa, resulting from failure of the transporter to reach the plasma membrane. These findings show that disruption of the human NaPi-IIa profoundly impairs overall renal phosphate reabsorption and proximal-tubule function and provide evidence of the critical role of NaPi-IIa in human renal phosphate handling.
Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in
...PLP1. Recently, homozygous mutations in
GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither
PLP1 nor
GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to
PLP1 and
GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in
HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo
E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support
E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.
Background and Objectives
Atypical hemolytic uremic syndrome (aHUS) is mostly attributed to dysregulation of the alternative complement pathway (ACP) secondary to disease-causing variants in ...complement components or regulatory proteins. Hereditary aHUS due to C3 disruption is rare, usually caused by heterozygous activating mutations in the
C3
gene, and transmitted as autosomal dominant traits. We studied the molecular basis of early-onset aHUS, associated with an unusual finding of a novel homozygous activating deletion in C3.
Design, Setting, Participants, & Measurements
A male neonate with eculizumab-responsive fulminant aHUS and C3 hypocomplementemia, and six of his healthy close relatives were investigated. Genetic analysis on genomic DNA was performed by exome sequencing of the patient, followed by targeted Sanger sequencing for variant detection in his close relatives. Complement components analysis using specific immunoassays was performed on frozen plasma samples from the patient and mother.
Results
Exome sequencing revealed a novel homozygous variant in exon 26 of
C3
(c.3322_3333del, p.Ile1108_Lys1111del), within the highly conserved thioester-containing domain (TED), fully segregating with the familial disease phenotype, as compatible with autosomal recessive inheritance. Complement profiling of the patient showed decreased C3 and FB levels, with elevated levels of the terminal membrane attack complex, while his healthy heterozygous mother showed intermediate levels of C3 consumption.
Conclusions
Our findings represent the first description of aHUS secondary to a novel homozygous deletion in C3 with ensuing unbalanced C3 over-activation, highlighting a critical role for the disrupted C3-TED domain in the disease mechanism.
Abstract
N
6
-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t
6
A) is a universal modification essential for translational accuracy and efficiency. The t
6
A pathway uses two ...sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in
YRDC
cause an extremely severe form of GAMOS whereas mutations in
GON7
, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.
To describe ocular findings in individuals with primary hyperoxaluria type 1 (PH1), focusing on the correlations between retinal anatomy and retinal function. To characterize the retinal alterations ...that occur at different disease stages by evaluating individuals with diverse degrees of renal impairment associated with PH1.
A cross-sectional study.
Patients diagnosed with PH1 based on clinical criteria and genetic testing, treated in the Pediatric Nephrology Unit of the Ruth Children’s Hospital, Rambam Health Care Campus, Haifa, Israel between 2013 and 2021.
The ophthalmological assessment included a slit-lamp biomicroscopy of the anterior and posterior segment or indirect ophthalmoscopy. Electroretinography was employed for assessment of the retinal function, and retinal imaging included spectral-domain OCT and fundus autofluorescence. A systematic evaluation of the disease stage was based on clinical criteria including physical examination, purposeful imaging (X-ray, echocardiography, and US abdomen), and laboratory tests as needed.
Anatomical and functional assessment of the retina in patients with PH1, and the relationship between retinal dysfunction and kidney impairment.
A total of 16 eyes were examined in the study of 8 children ranging in age from 4 to 19 years. Four eyes (25%) showed normal structural and functional retinal findings, 8 eyes (50%) presented functional impairment in the absence of pathological structural findings, and 4 eyes (25%) had advanced retinal damage that manifested as significant morphological and functional impairment. There was no direct relationship between the severity of the renal disease and the severity of the retinal phenotype.
Subjects with PH1 present varying severity levels of the retinal phenotype, with possible discrepancy between the clinical retinal morphology and the retinal function noted on electroretinography. These findings raise questions about the molecular basis of the retinal manifestations in PH1. The presence of functional impairment in the absence of evident crystal deposition in the retina suggests that, in addition to oxalate crystal accumulation, other biomolecular processes may play a role in the development of retinopathy.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
PDF
