ALLN-177, oral enzyme therapy for hyperoxaluria

PURPOSE: To evaluate the potential of ALLN-177, an orally administered, oxalate-specific enzyme therapy to reduce urine oxalate (UOx) excretion in patients with secondary hyperoxaluria. METHODS: Sixteen male and female subjects with both hyperoxaluria and a kidney stone history were enrolled in an open-label study. Subjects continued their usual diets and therapies. During a 3-day baseline period, two 24-h (24-h) urines were collected, followed by a 4-day treatment period with ALLN-177 (7,500 units/meal, 3 × day) when three 24-h urines were collected. The primary endpoint was the change in mean 24-h UOx from baseline. Safety assessments and 24-h dietary recalls were performed throughout. RESULTS: The study enrolled 5 subjects with enteric hyperoxaluria and 11 with idiopathic hyperoxaluria. ALLN-177 was well tolerated. Overall mean (SD) UOx decreased from 77.7 (55.9) at baseline to 63.7 (40.1) mg/24 h while on ALLN-177 therapy, with the mean reduction of 14 mg/24 h, (95% CI - 23.71, - 4.13). The calcium oxalate-relative urinary supersaturation ratio in the overall population decreased from a mean of 11.3 (5.7) to 8.8 (3.8) (- 2.8; 95% CI - 4.9, - 0.79). This difference was driven by oxalate reduction alone, but not any other urinary parameters. Mean daily dietary oxalate, calcium, and fluid intake recorded by frequent diet recall did not differ by study periods. CONCLUSION: ALLN-177 reduced 24-h UOx excretion, and was well tolerated. The results of this pilot study provided justification for further investigation of ALLN-177 in patients with secondary hyperoxaluria

Parathyroid hormone-stimulated calcium absorption in cTAL from vitamin D-deficient rabbits

Parathyroid hormone-stimulated calcium absorption in cTAL from vitamin D-deficient rabbits. Cortical thick ascending limbs of Henle's loop were dissected from the kidneys of chronically vitamin D-deficient or -replete rabbits and perfused in vitro. Unidirectional transepithelial calcium fluxes from lumen to bath were measured with 45Ca. The tubules were bathed in a solution containing 150mM sodium and perfused with a solution containing 60mM sodium to simulate conditions in the cortical thick ascending limb in vivo. Transepithelial voltages were equal across tubules from vitamin D-deficient and -replete rabbits. Likewise, baseline and parathyroid hormone-stimulated calcium fluxes were the same in tubules from the two groups. Because calcidiol and calcitriol were undetectable in the serum of the vitamin D-deficient rabbits, we suggest that neither of these endogenous vitamin D metabolites is essential in the regulation of calcium absorption in this portion of the rabbit nephron

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

Chronic kidney disease; Pediatric nephrology; UrologyMalaltia renal crònica; Nefrologia pediàtrica; UrologiaEnfermedad renal crónica; Nefrología pediátrica; UrologíaNedosiran 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

Serum albumin and hospitalization among pediatric patients with end-stage renal disease who started dialysis therapy.

BackgroundHypoalbuminemia is a strong predictor of hospitalization and mortality among adult dialysis patients. However, data are scant on the association between serum albumin and hospitalization among children new to dialysis.MethodsIn a retrospective cohort study of children 1-17&nbsp;years old with end-stage renal disease receiving&nbsp;dialysis therapy in a large US dialysis organization 2007-2011, we examined the association of serum albumin with hospitalization frequency and total hospitalization days using&nbsp;a negative binomial regression model.ResultsAmong 416 eligible patients, median (interquartile range) age was 14 (10-16) years and mean ± SD baseline serum albumin level was 3.7 ± 0.8&nbsp;g/dL. Two hundred sixty-six patients (64%) were hospitalized during follow-up with&nbsp;an incidence rate of 2.2 (95%CI, 1.9-2.4)&nbsp;admissions per patient-year. There was a U-shaped association between serum albumin and hospitalization frequency; hospitalization rates (95%CI) were 2.7 (2.2-3.2), 1.9 (1.5-2.4), 1.6 (1.3-1.9), and 2.7 (1.7-3.6) per patient-year among patients with serum albumin levels &lt; 3.5, 3.5- &lt; 4.0, 4.0- &lt; 4.5, and ≥ 4.5&nbsp;g/dL, respectively. Case mix-adjusted hospitalization incidence rate ratios (IRRs) (95%CI) were 1.63 (1.24-2.13), 1.32 (1.10-1.58), and 1.25 (1.06-1.49) at serum albumin levels 3.0, 3.5, and 4.5&nbsp;g/dL, respectively (reference: 4.0&nbsp;g/dL). Similar trends were observed in hospitalization days. These associations remained robust against further adjustment for laboratory variables associated with malnutrition and inflammation.ConclusionsBoth high and low serum albumin were associated with higher hospitalization in children starting dialysis. Because the observed association is novel and not fully explainable especially for high serum albumin levels, interpreting the results requires caution and further studies are needed to confirm and elucidate this association before clinical recommendations are made

Werther

Johann Wolfgang Goethe'nin Malumat'ta yayımlanan Werther adlı romanının ilk ve son tefrikalarıTefrikanın devamına rastlanmamış, tefrika yarım kalmıştır

Depressive Symptoms in Children with Chronic Kidney Disease

To assess depression in children with chronic kidney disease (CKD) and to determine associations with patient characteristics, intellectual and educational levels, and health related quality of life (HRQoL)

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome.METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants.RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving.CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.</p