4.6 Review

Improving Treatment Options for Primary Hyperoxaluria

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Review Urology & Nephrology

Perspectives in primary hyperoxaluria - historical, current and future clinical interventions

Kevin Shee et al.

Summary: Primary hyperoxalurias are a devastating family of diseases that eventually lead to end-stage renal disease. Current treatment paradigms are limited, but new therapeutics aim to target oxalate synthesis and metabolism pathways to reduce accumulation and deposition in the body.

NATURE REVIEWS UROLOGY (2022)

Article Pediatrics

The effect of lumasiran therapy for primary hyperoxaluria type 1 in small infants

Marie-Noelle Meaux et al.

Summary: This study describes the treatment outcomes of lumasiran therapy in 3 infants under 2 years of age. Lumasiran appears to be effective and well-tolerated in infants, but it does not completely prevent the onset of nephrocalcinosis in severe cases. Higher doses may be required in infants due to hepatic immaturity.

PEDIATRIC NEPHROLOGY (2022)

Article Transplantation

Clinical characterization of primary hyperoxaluria type 3 in comparison with types 1 and 2

Prince Singh et al.

Summary: Primary hyperoxaluria type 3 (PH3) is characterized by symptoms at a younger age compared to PH1 and PH2, with lower urine oxalate excretion and higher urine calcium levels. Stone events are similar across age groups and PH types, with a lower risk of kidney failure in PH3 patients compared to PH1 and PH2 by age 40. Long-term follow-up studies of larger cohorts are needed to further understand the PH3 phenotype.

NEPHROLOGY DIALYSIS TRANSPLANTATION (2022)

Article Pediatrics

Case Report: Sustained Efficacy of Lumasiran at 18 Months in Primary Hyperoxaluria Type 1

Benedetta Chiodini et al.

Summary: Lumasiran has shown to effectively reduce plasma oxalate and urinary excretion levels in patients with primary hyperoxaluria type 1, leading to clinical improvements and stable kidney function.

FRONTIERS IN PEDIATRICS (2022)

Article Urology & Nephrology

Primary Hyperoxaluria Type 3 Can Also Result in Kidney Failure: A Case Report

Prince Singh et al.

Summary: Primary hyperoxaluria (PH) is a genetic disorder that results in increased hepatic production of oxalate. PH type 3 (PH3) is the most recently identified subtype and can lead to kidney failure. Family history of the disease and marked hyperoxaluria can suggest the presence of PH3. Treatment options include hydration and medication.

AMERICAN JOURNAL OF KIDNEY DISEASES (2022)

Review Urology & Nephrology

New therapeutics for primary hyperoxaluria type 1

Pegah Dejban et al.

Summary: This review provides an update on emerging therapies for the treatment of Primary hyperoxaluria type 1 (PH1), a rare genetic disorder that causes hepatic overproduction of oxalate. The review highlights the use of RNA interference (RNAi) therapeutics, alternative approaches, and genetic editing tools as potential treatments for PH1. These novel treatments have shown efficacy in reducing urinary oxalate excretion in PH1 patients, which may lessen the need for combined kidney and liver transplantation and decrease morbidity and mortality.

CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION (2022)

Article Urology & Nephrology

Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Bernd Hoppe et al.

Summary: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and dose-response relationship of Nedosiran in healthy individuals and patients with PH. The results showed that single-dose Nedosiran demonstrated acceptable safety and evidence of pharmacodynamic effect in both PH1 and PH2 subpopulations.

KIDNEY INTERNATIONAL (2022)

Article Medicine, Research & Experimental

In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria

Rebeca Martinez-Turrillas et al.

Summary: This study demonstrates the efficacy of liver-specific inhibition of lactate dehydrogenase (LDH) using CRISPR-Cas9 systems for treating primary hyperoxalurias (PHs). The inhibition led to reduced levels of LDH in the liver, resulting in decreased urine oxalate levels and kidney damage without any signs of toxicity. The findings suggest that in vivo genome editing with CRISPR-Cas9 systems could be a valuable tool for improving therapeutic approaches for PH.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2022)

Article Chemistry, Medicinal

New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production

Maria Dolores Moya-Garzon et al.

Summary: The article describes the synthesis and biological evaluation of double glycolate oxidase/lactate dehydrogenase inhibitors containing a salicylic acid moiety, which are obtained through a two-step synthesis procedure and show potential therapeutic effects on primary hyperoxalurias.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2022)

Letter Urology & Nephrology

Is stiripentol truly effective for treating primary hyperoxaluria?

Cristina Martin-Higueras et al.

CLINICAL KIDNEY JOURNAL (2021)

Article Transplantation

Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria Type 1 and end-stage renal disease: a Phase II study

Bernd Hoppe et al.

Summary: In PH1 ESRD patients, long-term administration of OC5 was found to significantly reduce Pox concentrations, improve or stabilize cardiac function and clinical status, without increasing dialysis frequency. OC5 was safe and well-tolerated, showing promising results for potential clinical impact.

NEPHROLOGY DIALYSIS TRANSPLANTATION (2021)

Article Pharmacology & Pharmacy

Lumasiran: First Approval

Lesley J. Scott et al.

Summary: Lumasiran is a drug developed for the treatment of primary hyperoxaluria type 1 by targeting a specific gene to inhibit the synthesis of toxic metabolites. It received approvals in the EU and USA, marking its global recognition.
Article Urology & Nephrology

Hepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria

Gema Ariceta et al.

Summary: Inhibition of LDHA by RNAi is a safe and liver-specific therapeutic mechanism for treating all types of PH, as shown by nonclinical and clinical data.

KIDNEY INTERNATIONAL REPORTS (2021)

Article Urology & Nephrology

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

Yaacov Frishberg et al.

Summary: This study evaluated the safety and pharmacodynamic characteristics of Lumasiran in patients with primary hyperoxaluria type 1, showing that Lumasiran has an acceptable safety profile and can reduce urinary oxalate excretion in patients to near-normal levels.

CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY (2021)

Article Medicine, General & Internal

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1

Sander F. Garrelfs et al.

Summary: Primary hyperoxaluria type 1 is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. This trial tested the efficacy of lumasiran, an RNAi therapeutic agent, in reducing hepatic oxalate production. The results showed that lumasiran significantly reduced urinary oxalate excretion, alleviating the cause of kidney failure in PH1 patients.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

Review Pediatrics

Transplantation outcomes in patients with primary hyperoxaluria: a systematic review

Elisabeth L. Metry et al.

Summary: The study suggests that combined liver-kidney transplantation leads to superior kidney graft survival compared to kidney transplantation alone. However, evidence for the advantages of sequentially performed liver-kidney transplantation or kidney transplantation in pyridoxine-responsive patients is scarce, emphasizing the need for further studies.

PEDIATRIC NEPHROLOGY (2021)

Article Urology & Nephrology

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

Kevin Shee et al.

Summary: Nedosiran has shown promising results in decreasing plasma oxalate levels and reducing the frequency of hemodialysis sessions in a patient with PH1, potentially delaying the need for combined kidney and liver transplant.

UROLOGY (2021)

Article Surgery

Primary hyperoxaluria diagnosed after kidney transplant: A review of the literature and case report of aggressive renal replacement therapy and lumasiran to prevent allograft loss

Hillarey K. Stone et al.

Summary: Primary hyperoxaluria type 1 is a rare genetic disorder that can be easily missed and lead to poor outcomes post-transplant, highlighting the importance of early detection and intervention to prevent adverse consequences in patients with chronic kidney disease.

AMERICAN JOURNAL OF TRANSPLANTATION (2021)

Letter Cardiac & Cardiovascular Systems

Oxalic Cardiomyopathy Could it Influence Treatment Plans in Patients With Primary Hyperoxaluria Type 1?

Alessandro Di Toro et al.

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY (2021)

Article Chemistry, Medicinal

Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria

Jinyue Ding et al.

Summary: This study investigated the potential advantage of dual inhibition of glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) in treating primary hyperoxaluria (PH), developing a series of novel dual GO/LDHA inhibitors. However, limited by poor liver exposure, these dual inhibitors failed to show significant PD modulation in an in vivo mouse model, highlighting challenges in optimizing liver exposures for diacid containing compounds and the limited benefit of dual GO/LDHA inhibitors over single agents in an in vitro setting.

ACS MEDICINAL CHEMISTRY LETTERS (2021)

Article Urology & Nephrology

Primary Hyperoxaluria Type 1 (PH1) Presenting With End-Stage Kidney Disease and Cutaneous Manifestations in Adulthood: A Case Report

Penelope Poyah et al.

Summary: This case report describes an adult presentation of primary hyperoxaluria type 1 (PH1) and highlights the importance of timely workup of metabolic causes of recurrent nephrolithiasis or nephrocalcinosis in adults to facilitate early diagnosis and treatment.

CANADIAN JOURNAL OF KIDNEY HEALTH AND DISEASE (2021)

Article Pediatrics

Stiripentol fails to lower plasma oxalate in a dialysis-dependent PH1 patient

Caroline Kempf et al.

PEDIATRIC NEPHROLOGY (2020)

Review Urology & Nephrology

Stiripentol identifies a therapeutic target to reduce oxaluria

Emmanuel Letavernier et al.

CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION (2020)

Article Ophthalmology

The Ocular Phenotype in Primary Hyperoxaluria Type 1

Johannes Birtel et al.

AMERICAN JOURNAL OF OPHTHALMOLOGY (2019)

Article Medicine, Research & Experimental

Stiripentol protects against calcium oxalate nephrolithiasis and ethylene glycol poisoning

Marine Le Dudal et al.

JOURNAL OF CLINICAL INVESTIGATION (2019)

Article Urology & Nephrology

Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up

Sander F. Garrelfs et al.

KIDNEY INTERNATIONAL (2019)

Article Chemistry, Medicinal

Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1

Maria Dolores Moya-Garzon et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

Article Pediatrics

Metabolite diagnosis of primary hyperoxaluria type 3

Lawrence Greed et al.

PEDIATRIC NEPHROLOGY (2018)

Article Urology & Nephrology

Metabolic profile and impact of diet in patients with primary hyperoxaluria

Roswitha Siener et al.

INTERNATIONAL UROLOGY AND NEPHROLOGY (2018)

Review Pharmacology & Pharmacy

Novel therapeutic approaches in primary hyperoxaluria

Alexander Weigert et al.

EXPERT OPINION ON EMERGING DRUGS (2018)

Article Surgery

Combined Liver-Kidney Transplantation for Primary Hyperoxaluria Type 2: A Case Report

T. Dhondup et al.

AMERICAN JOURNAL OF TRANSPLANTATION (2018)

Article Endocrinology & Metabolism

Molecular therapy of primary hyperoxaluria

Cristina Martin-Higueras et al.

JOURNAL OF INHERITED METABOLIC DISEASE (2017)

Article Medicine, Research & Experimental

Generation of a Vero-Based Packaging Cell Line to Produce SV40 Gene Delivery Vectors for Use in Clinical Gene Therapy Studies

Miguel G. Toscano et al.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2017)

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Assessment of the low inhibitory specificity of oxamate, aminooxyacetate and dichloroacetate on cancer energy metabolism

Rafael Moreno-Sanchez et al.

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS (2017)

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Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure

Fang Zhao et al.

CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY (2016)

Article Biotechnology & Applied Microbiology

Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I

Cristina Martin-Higueras et al.

MOLECULAR THERAPY (2016)

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Generation and characterization of human iPSC lines derived from a Primary Hyperoxaluria Type I patient with p.I244T mutation

Natalia Zapata-Linares et al.

STEM CELL RESEARCH (2016)

Review Surgery

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Sally-Anne Hulton

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Vitamin B6 in Primary Hyperoxaluria I: First Prospective Trial after 40 Years of Practice

Heike Hoyer-Kuhn et al.

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Article Multidisciplinary Sciences

Pharmacologic rescue of an enzyme-trafficking defect in primary hyperoxaluria 1

Non Miyata et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2014)

Article Medicine, Research & Experimental

Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1 beta secretion

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Primary Hyperoxaluria

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Primary hyperoxalurias: Disorders of glyoxylate detoxification

Eduardo Salido et al.

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An update on primary hyperoxaluria

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Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment

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Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization with Oxalobacter

Marguerite Hatch et al.

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Primary Hyperoxaluria Type III Gene HOGA1 (Formerly DHDPSL) as a Possible Risk Factor for Idiopathic Calcium Oxalate Urolithiasis

Carla G. Monico et al.

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Article Biotechnology & Applied Microbiology

Phenotypic Correction of a Mouse Model for Primary Hyperoxaluria With Adeno-associated Virus Gene Transfer

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Article Genetics & Heredity

Mutations in DHDPSL Are Responsible For Primary Hyperoxaluria Type III

Ruth Belostotsky et al.

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Transplantation Outcomes in Primary Hyperoxaluria

E. J. Bergstralh et al.

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S. Tamir Rashid et al.

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Benjamin A. Vervaet et al.

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In Vivo and in Vitro Examination of Stability of Primary Hyperoxaluria-associated Human Alanine: Glyoxylate Aminotransferase

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Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy

Mark E. Williams et al.

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Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1

B. Hoppe et al.

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Article Urology & Nephrology

Oxalobacter sp reduces urinary oxalate excretion by promoting enteric oxalate secretion

M Hatch et al.

KIDNEY INTERNATIONAL (2006)

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Intestinal transport of an obdurate anion: oxalate

M Hatch et al.

UROLOGICAL RESEARCH (2005)

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The primary hyperoxalurias: An algorithm for diagnosis

DS Milliner

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Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome

CS van Woerden et al.

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Article Gastroenterology & Hepatology

Combined liver-kidney and kidney-alone transplantation in primary hyperoxaluria

CG Monico et al.

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