Nedosiran Dramatically Reduces Serum Oxalate in Dialysis-Dependent Primary Hyperoxaluria 1: A Compassionate Use Case Report

Shee, Kevin; Ahn, JoongHo; Hamouche, Fadl; Mena, Jorge; Chi, Thomas; Stoller, Marshall L.

doi:10.1016/j.urology.2021.03.014

Cited by 16 publications

(18 citation statements)

References 13 publications

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“…One patient with PH1 was given stiripental with significant decrease in urine oxalate. An RNAi of LDH was developed (Nedosiran) and was used in a single patient with ESKD with significant decrease in blood oxalate levels [ 72 ]. A study of this agent in patients with both PH1 and PH2 is ongoing (NCT03847909).…”

Section: Treatmentmentioning

confidence: 99%

Oxalate nephropathy: a review

Rosenstock

Joab

Devita

et al. 2021

Clinical Kidney Journal

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This review describes the clinical and pathological features of oxalate nephropathy (ON), defined as a syndrome of decreased renal function associated with deposition of calcium oxalate crystals in kidney tubules. We review the different causes of hyperoxaluria, including primary hyperoxaluria, enteric hyperoxaluria and ingestion related hyperoxaluria. Recent case series of biopsy proven ON are reviewed in detail as well as the implications of these series. The possibility of antibiotic use predisposing to ON is discussed. Therapies for hyperoxaluria and ON are reviewed with an emphasis on newer treatments available and in development. Promising research avenues to explore in this area are discussed.

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Section: Treatmentmentioning

confidence: 99%

Oxalate nephropathy: a review

Rosenstock

Joab

Devita

et al. 2021

Clinical Kidney Journal

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“…RNAi: The new RNAi-based therapies, lumasiran and nedosiran are promising agents for these difficult patients [ 30 , 31 ]. Lumasiran inhibits glyoxylate production by blocking glycolate oxidase (GO), acting as a substrate reducing agent.…”

Section: Management Of Infantile Oxalosismentioning

confidence: 99%

“…Data in patients with severe kidney failure are about to appear [ 30 ]. Nedosiran, which inhibits lactate dehydrogenase-A, the final metabolic step from glyoxylate to oxalate, has shown a significant lowering effect on plasma oxalate levels in a compassionate-use PH1 patient on dialysis [ 31 ]. Trials with nedosiran are currently being conducted.…”

Section: Management Of Infantile Oxalosismentioning

confidence: 99%

Primary hyperoxaluria: the pediatric nephrologist's point of view

Ben-Shalom

Garrelfs

Groothoff

2022

Clinical Kidney Journal

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The clinical presentation of primary hyperoxaluria in children ranges from mildly symptomatic nephrocalcinosis to very early onset end-stage kidney failure with systemic oxalosis, a devastating complication. We review the various manifestations of pediatric hyperoxaluria, treatment options for children with preserved kidney function and appropriate dialysis regimens. Liver or combined liver/kidney transplantation is currently the only definitive treatment for primary hyperoxaluria type 1, but novel RNA interference treatments offer hope for the future. Finally, we address the medical and ethical dilemmas facing pediatricians treating children with hyperoxaluria.

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“…Pre-clinical experiments in a mouse model of PH1 and PH2 treated with LDHA-specific siRNA resulted in an efficient reduction of CaOx excretion while preventing crystal deposition in mouse kidneys [77]. The first phase of clinical trials of Nedosiran on PH1 and PH2 patients demonstrated a positive effect on Ox production [78,79], however, in phase 2 trials, PH2 and PH3 patients did not achieve the primary endpoint of significant urinary oxalate lowering effect [80,81].…”

Section: Ph Therapymentioning

confidence: 99%

Catabolism of Hydroxyproline in Vertebrates: Physiology, Evolution, Genetic Diseases and New siRNA Approach for Treatment

Belostotsky¹,

Frishberg²

2022

IJMS

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Hydroxyproline is one of the most prevalent amino acids in animal proteins. It is not a genetically encoded amino acid, but, rather, it is produced by the post-translational modification of proline in collagen, and a few other proteins, by prolyl hydroxylase enzymes. Although this post-translational modification occurs in a limited number of proteins, its biological significance cannot be overestimated. Considering that hydroxyproline cannot be re-incorporated into pro-collagen during translation, it should be catabolized following protein degradation. A cascade of reactions leads to production of two deleterious intermediates: glyoxylate and hydrogen peroxide, which need to be immediately converted. As a result, the enzymes involved in hydroxyproline catabolism are located in specific compartments: mitochondria and peroxisomes. The particular distribution of catabolic enzymes in these compartments, in different species, depends on their dietary habits. Disturbances in hydroxyproline catabolism, due to genetic aberrations, may lead to a severe disease (primary hyperoxaluria), which often impairs kidney function. The basis of this condition is accumulation of glyoxylate and its conversion to oxalate. Since calcium oxalate is insoluble, children with this rare inherited disorder suffer from progressive kidney damage. This condition has been nearly incurable until recently, as significant advances in substrate reduction therapy using small interference RNA led to a breakthrough in primary hyperoxaluria type 1 treatment.

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Nedosiran Dramatically Reduces Serum Oxalate in Dialysis-Dependent Primary Hyperoxaluria 1: A Compassionate Use Case Report

Cited by 16 publications

References 13 publications

Oxalate nephropathy: a review

Oxalate nephropathy: a review

Primary hyperoxaluria: the pediatric nephrologist's point of view

Catabolism of Hydroxyproline in Vertebrates: Physiology, Evolution, Genetic Diseases and New siRNA Approach for Treatment

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