2026-07-03 | Primary hyperoxaluria type 1-current practice in the siRNA era: an ERA Genes & Kidney Working Group survey.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder leading to the formation of kidney stones, nephrocalcinosis, and kidney failure. Besides, PH1 poses the risk of developing systemic oxalosis, a life-threatening condition with oxalate deposits in multiple organ systems. The rarity of the disorder combined with recent major additions to therapeutic options based on small interfering RNA (siRNA) therapeutics make a formal assessment of current practice and implementation of treatment recommendations an important asset. An international questionnaire survey was conducted among medical doctors involved in the treatment of patients with chronic kidney disease. The survey included 32 questions addressing demographics, diagnostics and therapeutics, and educational needs related to the care for PH1 patients. 176 participants from 43 countries completed the survey, the majority of them were from Europe. The results indicate clear shortcomings in the availability of recommended diagnostics, especially with regards to plasma oxalate. Genetic testing strategies often do not include patients who may have PH1, e.g. when the underlying cause of kidney failure is unknown or in patients with nephrolithiasis or nephrocalcinosis. Treatment modalities are only partly harmonized and intensified dialysis is not fully implemented across centers. Strategies toward combination of conventional therapeutics such as hyperhydration and pyridoxine with new siRNA therapeutics depend on the treating physician's expertise. The survey identifies clear needs regarding implementation of current treatment recommendations as well as important educational gaps. The advent of targeted treatment opportunities for PH1 comes with an increased need to provide guidance to the field. Filling the existing gaps will ensure that a growing number of patients get access to optimal care and novel life-changing therapies.
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2026-06-16 | In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.
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2026-06-08 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation.
Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver-kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions - high fluid intake, crystallization inhibitors, and pyridoxine - can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
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