Clinical features and mutational spectrum of Chinese patients with primary hyperoxaluria type 2.

Primary hyperoxaluria type 2 (PH2) is a rare hereditary disease that causes nephrolithiasis, nephrocalcinosis and kidney failure. This study aimed to investigate the clinical features and mutational spectrum of Chinese patients with PH2. A retrospective cohort study was performed on PH2 patients admitted to our center over seven years. We also systematically reviewed all the articles on Chinese PH2 patients published from January 2000 to May 2023 and conducted a meta-analysis. A total of 25 PH2 patients (10 from our center and 15 from published studies) were included in this study. The median age of onset in patients from our center was 8.50 (1.00, 24.00) years, and 50% were male. Among the full cohort of 25 Chinese patients, the median age of onset was 8.00 (0.40, 26.00) years, and 64% of them were male. Seven patients progressed to end-stage kidney disease, with a median age of 27.50 (12, 31) years. The cumulative renal survival rates were 100%, 91.67%, 45.83% and 30.56% at 10, 20, 30 and 40 years of age, respectively. A total of 18 different variants were identified, and c.864_865del was the dominant variant, accounting for 57.69% of the total alleles. Patients who were heterozygous for c.864_865del were more susceptible to nephrocalcinosis than those who were homozygous for c.864_865del and those harboring other mutations (83.33% versus 33.3% and 0%, respectively) (p = 0.025). The clinical features and mutational spectrum of Chinese PH2 patients were described. This study helps to expand awareness of the phenotypes and genotypes of Chinese PH2 patients and contributes to the improvement of diagnostic and treatment strategies for PH2 patients.

Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs.

Primary hyperoxalurias (PHs) are inherited metabolic disorders marked by enzymatic cascade disruption, leading to excessive oxalate production that is subsequently excreted in the urine. Calcium oxalate deposition in the renal tubules and interstitium triggers renal injury, precipitating systemic oxalate build-up and subsequent secondary organ impairment. Recent explorations of novel therapeutic strategies have challenged and necessitated the reassessment of established management frameworks. The execution of diverse clinical trials across various medication classes has provided new insights and knowledge. With the evolution of PH treatments reaching a new milestone, prompt and accurate diagnosis is increasingly critical. Developing early, effective management and treatment plans is essential to improve the long-term quality of life for PH patients.

Expanding the Genetic Spectrum of AGXT Gene Variants in Egyptian Patients with Primary Hyperoxaluria Type I.

Introduction: Approximately 80% of primary hyperoxaluria cases are caused by primary hyperoxaluria type 1 (PH1, OMIM# 259900), which is characterized by pathogenic variants in the AGXT gene, resulting in deficiency of the liver-specific enzyme alanine-glyoxylate aminotransferase (AGT). This leads to increased production of oxalate, which cannot be effectively eliminated from the body, resulting in its accumulation primarily in the kidneys and other organs. Subjects and Methods: This study included 17 PH1 Egyptian patients from 12 unrelated families, recruited from the Inherited Kidney Disease Outpatient Clinic and the Dialysis Units, Cairo University Hospitals, during the period from January 2018 to December 2019, aiming to identify the pathogenic variants in the AGXT gene. Results: Six different variants were detected. These included three frameshift and three missense variants, all found in homozygosity within the respective families. The most common variant was c.121G>A;p.(Gly41Arg) detected in four families, followed by c.725dup;p.(Asp243GlyfsTer12) in three families, c.33dup;p.(Lys12Glnfs156) in two families, and c.731T >C;p.(Ile244Thr), c.33delC;p.(Lys12Argfs34), and c.568G>A;p.(Gly190Arg) detected in one family each. Conclusion: Consanguineous Egyptian families with history of renal stones or renal disease suspicious of primary hyperoxaluria should undergo AGXT genetic sequencing, specifically targeting exons 1 and 7, as variants in these two exons account for >75% of disease-causing variants in Egyptian patients with confirmed PH1.

A molecular journey on the pathogenesis of primary hyperoxaluria.

PURPOSE OF REVIEW: Primary hyperoxalurias (PHs) are rare disorders caused by the deficit of liver enzymes involved in glyoxylate metabolism. Their main hallmark is the increased excretion of oxalate leading to the deposition of calcium oxalate stones in the urinary tract. This review describes the molecular aspects of PHs and their relevance for the clinical management of patients. RECENT FINDINGS: Recently, the study of PHs pathogenesis has received great attention. The development of novel in vitro and in vivo models has allowed to elucidate how inherited mutations lead to enzyme deficit, as well as to confirm the pathogenicity of newly-identified mutations. In addition, a better knowledge of the metabolic consequences in disorders of liver glyoxylate detoxification has been crucial to identify the key players in liver oxalate production, thus leading to the identification and validation of new drug targets. SUMMARY: The research on PHs at basic, translational and clinical level has improved our knowledge on the critical factors that modulate disease severity and the response to the available treatments, leading to the development of new drugs, either in preclinical stage or, very recently, approved for patient treatment.

Lumasiran: A Review in Primary Hyperoxaluria Type 1.

Lumasiran (Oxlumo®), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is approved in several countries for patients of any age and stage of kidney function with primary hyperoxaluria type 1 (PH1). Approval was based on results from the phase III ILLUMINATE trials. In the double-blind, placebo-controlled, ILLUMINATE-A trial, subcutaneous lumasiran was significantly more effective than placebo in reducing 24-h urinary oxalate excretion in patients aged ≥ 6 years with PH1; this effect was sustained for ≥ 36 months in ongoing longer-term analyses. In the single-arm ILLUMINATE-B trial, lumasiran reduced urinary oxalate:creatinine ratios and plasma oxalate levels in patients aged < 6 years with PH1. In the single-arm ILLUMINATE-C trial, lumasiran reduced plasma oxalate levels in patients with PH1 receiving dialysis as well as those not receiving dialysis. In secondary and exploratory analyses of these trials, nephrocalcinosis grade, kidney stone event rates and estimated glomerular filtration rates were either stable or improved with lumasiran. Lumasiran had an acceptable tolerability profile that remained consistent in longer-term analyses; the most common adverse events were mild and transient injection-site reactions. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1.

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that leads to excess oxalate in urine or plasma requiring removal by the kidneys. This overproduction is damaging and can lead to kidney failure. Management of PH1 is typically not curative, eventually ending in kidney and/or liver transplantation. Lumasiran (Oxlumo^®) is the first medicine to be approved in several countries for use in patients with PH1, regardless of their age or level of kidney function. It reduces liver oxalate production, lessening damage to the kidneys and potentially reducing the need for organ transplantation. In clinical trials, lumasiran was effective in reducing oxalate levels (in urine and/or plasma) in patients of all ages with PH1, and irrespective of whether they were receiving dialysis or not. Lumasiran either improved or stabilized the severity of calcium deposition in the kidneys, number of kidney stone events and kidney function. Lumasiran had an acceptable tolerability profile; the most common side effects were mild injection-site reactions that resolved quickly. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1.

Insights into the pathogenesis of primary hyperoxaluria type I from the structural dynamics of alanine:glyoxylate aminotransferase variants.

Primary hyperoxaluria type I (PH1) is caused by deficient alanine:glyoxylate aminotransferase (AGT) activity. PH1-causing mutations in AGT lead to protein mistargeting and aggregation. Here, we use hydrogen-deuterium exchange (HDX) to characterize the wild-type (WT), the LM (a polymorphism frequent in PH1 patients) and the LM G170R (the most common mutation in PH1) variants of AGT. We provide the first experimental analysis of AGT structural dynamics, showing that stability is heterogeneous in the native state and providing a blueprint for frustrated regions with potentially functional relevance. The LM and LM G170R variants only show local destabilization. Enzymatic transamination of the pyridoxal 5-phosphate cofactor bound to AGT hardly affects stability. Our study, thus, supports that AGT misfolding is not caused by dramatic effects on structural dynamics.

[Primary hyperoxaluria type 1-a rare hereditary metabolic disorder as cause of livedo racemosa]. / Primäre Hyperoxalurie Typ 1 ­ eine seltene hereditäre Stoffwechselstörung als Ursache einer Livedo racemosa.

Livedo racemosa is characterized by a bizarrely configurated lightning figure-like appearance with striated to reticulated, livid erythematous macules and results from a reduced perfusion of the respective skin area, which can have different underlying pathophysiologies. A rare but relevant cause, especially in young patients with end-stage kidney failure, is primary hyperoxaluria type 1 (PH1), a hereditary metabolic disorder in which oxalate accumulates in the body.

Nephrocalcinosis can disappear in infants receiving early lumasiran therapy.

BACKGROUND: Lumasiran is the first RNA interference (RNAi) therapy of primary hyperoxaluria type 1 (PH1). Here, we report on the rapid improvement and even disappearance of nephrocalcinosis after early lumasiran therapy. CASE-DIAGNOSIS/TREATMENT: In patient 1, PH1 was suspected due to incidental discovery of nephrocalcinosis stage 3 in a 4-month-old boy. Bilateral nephrocalcinosis stage 3 was diagnosed in patient 2 at 22 months concomitantly to acute pyelonephritis. Urinary oxalate (UOx) and glycolate (UGly) were increased in both patients allowing to start lumasiran therapy before genetic confirmation. Nephrocalcinosis started to improve and disappeared after 27 months and 1 year of treatment in patients 1 and 2, respectively. CONCLUSION: These cases illustrate the efficacy of early lumasiran therapy in infants to improve and even normalize nephrocalcinosis. As proposed in the 2023 European guidelines, the interest of starting treatment quickly without waiting for genetic confirmation may have an impact on long-term outcomes.

Comprehensive evaluation of patients with primary hyperoxaluria type 1: A nationwide study.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is characterized by increased endogenous oxalate production and deposition as calcium oxalate crystals. The main manifestations are nephrocalcinosis/nephrolithiasis, causing impaired kidney function. We aimed to evaluate the clinical characteristics and overall outcomes of paediatric PH1 patients in Turkey. METHODS: This is a nationwide, multicentre, retrospective study evaluating all available paediatric PH1 patients from 15 different paediatric nephrology centres in Turkey. Detailed patient data was collected which included demographic, clinical and laboratory features. Patients were classified according to their age and characteristics at presentation: patients presenting in the first year of life with nephrocalcinosis/nephrolithiasis (infantile oxalosis, Group 1), cases with recurrent nephrolithiasis diagnosed during childhood (childhood-onset PH1, Group 2), and asymptomatic children diagnosed with family screening (Group 3). RESULTS: Forty-eight patients had a mutation consistent with PH1. The most common mutation was c.971_972delTG (25%). Infantile oxalosis patients had more advanced chronic kidney disease (CKD) or kidney failure necessitating dialysis (76.9% vs. 45.5%). These patients had much worse clinical course and mortality rates seemed to be higher (23.1% vs. 13.6%). Patients with fatal outcomes were the ones with significant comorbidities, especially with cardiovascular involvement. Patients in Group 3 were followed with better outcomes, with no kidney failure or mortality. CONCLUSION: PH1 is not an isolated kidney disease but a systemic disease. Family screening helps to preserve kidney function and prevent systemic complications. Despite all efforts made with traditional treatment methods including transplantation, our results show devastating outcomes or mortality.

Efficient and safe therapeutic use of paired Cas9-nickases for primary hyperoxaluria type 1.

The therapeutic use of adeno-associated viral vector (AAV)-mediated gene disruption using CRISPR-Cas9 is limited by potential off-target modifications and the risk of uncontrolled integration of vector genomes into CRISPR-mediated double-strand breaks. To address these concerns, we explored the use of AAV-delivered paired Staphylococcus aureus nickases (D10ASaCas9) to target the Hao1 gene for the treatment of primary hyperoxaluria type 1 (PH1). Our study demonstrated effective Hao1 gene disruption, a significant decrease in glycolate oxidase expression, and a therapeutic effect in PH1 mice. The assessment of undesired genetic modifications through CIRCLE-seq and CAST-Seq analyses revealed neither off-target activity nor chromosomal translocations. Importantly, the use of paired-D10ASaCas9 resulted in a significant reduction in AAV integration at the target site compared to SaCas9 nuclease. In addition, our study highlights the limitations of current analytical tools in characterizing modifications introduced by paired D10ASaCas9, necessitating the development of a custom pipeline for more accurate characterization. These results describe a positive advance towards a safe and effective potential long-term treatment for PH1 patients.

Distinguishing characteristics of pediatric patients with primary hyperoxaluria type 1 in PEDSnet.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism that causes oxalate deposition, leading to recurrent calcium oxalate kidney stones, chronic kidney disease and systemic oxalosis, which produces a broad range of serious life-threatening complications. Patients with PH1 have delayed diagnosis due to the rarity of the disease and the overlap with early-onset kidney stone disease not due to primary hyperoxaluria. OBJECTIVE: The objective of this study was to determine the clinical features of individuals <21 years of age with PH1 that precede its diagnosis. We hypothesized that a parsimonious set of features could be identified that differentiate patients with PH1 from patients with non-primary hyperoxaluria-associated causes of early-onset kidney stone disease. STUDY DESIGN: We determined the association between clinical characteristics and PH1 diagnosis in a case-control study conducted between 2009 and 2021 in PEDSnet, a clinical research network of eight US pediatric health systems. Each patient with genetically confirmed PH1 was matched by sex and PEDSnet institution to up to 4 control patients with kidney stones without PH of any type. We obtained patient characteristics and diagnostic test results occurring before to less than 6 months after study entrance from a centralized database query and from manual chart review. Differences were examined using standardized differences and multivariable regression. RESULTS: The study sample included 37 patients with PH1 and 147 controls. Patients with PH1 were younger at diagnosis (median age of 3 vs 13.5 years); 75 % of children with PH1 were less than 8 years-old. Patients with PH1 were more likely to have combinations of nephrocalcinosis on ultrasound or CT (43 % vs 3 %), lower eGFR at diagnosis (median = 52 mL/min/1.73 m2 vs 114 mL/min/1.73 m2), and have normal mobility. Patients with PH1 had higher proportion of calcium oxalate monohydrate kidney stones than controls (median = 100 % vs 10 %). There were no differences in diagnosis of failure to thrive, stone size, or echocardiography results. CONCLUSIONS: Children with PH1 are characterized by presentation before adolescence, nephrocalcinosis, decreased eGFR at diagnosis, and calcium oxalate monohydrate stone composition. If externally validated, these characteristics could facilitate earlier diagnosis and treatment of children with PH1.

Primary Hyperoxaluria Screening and Monitoring: Quantitative Measurement of Plasma Oxalate by Gas Chromatography-Mass Spectrometry With High Sensitivity.

Background: Plasma oxalate measurements can be used for the screening and therapeutic monitoring of primary hyperoxaluria. We developed a gas chromatography-mass spectrometry (GC-MS) assay for plasma oxalate measurements with high sensitivity and suitable testing volumes for pediatric populations. Methods: Plasma oxalate was extracted, derivatized, and analyzed by GC-MS. We measured the ion at m/z 261.10 to quantify oxalate and the 13C2-oxalate ion (m/z: 263.15) as the internal standard. Method validation included determination of the linear range, limit of blank, limit of detection, lower limit of quantification, precision, recovery, carryover, interference, and dilution effect. The cut-off value between primary and non-primary hyperoxaluria in a pediatric population was analyzed. Results: The detection limit was 0.78 µmol/L, and the linear range was up to 80.0 µmol/L. The between-day precision was 5.7% at 41.3 µmol/L and 13.1% at 1.6 µmol/L. The carryover was <0.2%. The recovery rate ranged from 90% to 110%. Interference analysis showed that Hb did not interfere with plasma oxalate quantification, whereas intralipids and bilirubin caused false elevation of oxalate concentrations. A cut-off of 13.9 µmol/L showed 63% specificity and 77% sensitivity, whereas a cut-off of 4.15 µmol/L showed 100% specificity and 20% sensitivity. The minimum required sample volume was 250 µL. The detected oxalate concentrations showed interference from instrument conditioning, sample preparation procedures, medications, and various clinical conditions. Conclusions: GC-MS is a sensitive assay for quantifying plasma oxalate and is suitable for pediatric patients. Plasma oxalate concentrations should be interpreted in a clinical context.

Clinical characteristics, genetic profile and short-term outcomes of children with primary hyperoxaluria type 2: a nationwide experience.

BACKGROUND: Three types of primary hyperoxaluria (PH) are recognized. However, data on PH type 2 (PH2), caused by defects in the GRHPR gene, are limited. METHODS: We reviewed the medical records of patients < 18 years of age with genetically-proven PH2 from seven centres across India to identify the age of onset, patterns of clinical presentation, short-term outcomes and genetic profile, and to determine if genotype-phenotype correlation exists. RESULTS: We report 20 patients (all with nephrolithiasis or nephrocalcinosis) diagnosed to have PH2 at a median (IQR) age of 21.5 (7, 60) months. Consanguinity and family history of kidney stones were elicited in nine (45%) and eight (40%) patients, respectively. The median (IQR) serum creatinine at PH2 diagnosis was 0.45 (0.29, 0.56) mg/dL with the corresponding estimated glomerular filtration rate being 83 (60, 96) mL/1.73 m2/min. A mutational hotspot (c.494 G > A), rare in Caucasians, was identified in 12 (60%) patients. An intronic splice site variant (c.735-1G > A) was noted in five (25%) patients. Four (20%) patients required surgical intervention for stone removal. Major adverse kidney events (mortality or chronic kidney disease (CKD) stages 3-5) were noted in six (30%) patients at a median (IQR) follow-up of 12 (6, 27) months. Risk factors for CKD progression and genotype-phenotype correlation could not be established. CONCLUSIONS: PH2 should no longer be considered an innocuous disease, but rather a potentially aggressive disease with early age of presentation, and possible rapid progression to CKD stages 3-5 in childhood in some patients. A mutational hotspot (c.494 G > A variant) was identified in 60% of cases, but needs further exploration to decipher the genotype-phenotype correlation.

Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1. METHODS: For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6). RESULTS: Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups. CONCLUSIONS: Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

In vivo base editing rescues primary hyperoxaluria type 1 in rats.

Primary hyperoxaluria type 1 (PH1) is a childhood-onset autosomal recessive disease, characterized by nephrocalcinosis, multiple recurrent urinary calcium oxalate stones, and a high risk of progressive kidney damage. PH1 is caused by inherent genetic defects of the alanine glyoxylate aminotransferase (AGXT) gene. The in vivo repair of disease-causing genes was exceedingly inefficient before the invention of base editors which can efficiently introduce precisely targeted base alterations without double-strand DNA breaks. Adenine base editor (ABE) can precisely convert A·T to G·C with the assistance of specific guide RNA. Here, we demonstrated that systemic delivery of dual adeno-associated virus encoding a split-ABE8e could artificially repair 13% of the pathogenic allele in AgxtQ84X rats, a model of PH1, alleviating the disease phenotype. Specifically, ABE treatment partially restored the expression of alanine-glyoxylate-aminotransferase (AGT), reduced endogenous oxalate synthesis and alleviated calcium oxalate crystal deposition. Western blot and immunohistochemistry confirmed that ABE8e treatment restored AGT protein expression in hepatocytes. Moreover, the precise editing efficiency in the liver remained stable six months after treatment. Thus, our findings provided a prospect of in vivo base editing as a personalized and precise medicine for PH1 by directly correcting the mutant Agxt gene.

Nedosiran: First Approval.

Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for the treatment of primary hyperoxaluria (PH). It reduces oxalate overproduction by inhibiting the expression of the hepatic lactate dehydrogenase (LDH) enzyme. Nedosiran received its first approval on 29 September 2023 in the USA to lower urinary oxalate levels in children aged ≥ 9 years and adults with PH type 1 (PH1) and relatively preserved kidney function [e.g. estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2]. This article summarizes the milestones in the development of nedosiran leading to this first approval for PH1.

Primary hyperoxaluria: a case series.

BACKGROUND: Primary hyperoxaluria (PH) is a rare genetic disorder characterized by the excessive production and accumulation of oxalate. We present five cases of PH, each exhibiting varying manifestations of the disorder including a case presenting as postpartum kidney failure. Notably, three of these cases involve a previously unreported mutation. CASE PRESENTATIONS: We evaluated five Indian patients who presented with varying manifestations of PH. The first case, a 30 year old woman, presented as post-partum kidney failure and was found to be having oxalate nephropathy precipitated by dietary oxalate overload in the setting of previously undiagnosed PH. Genetic analysis revealed a previously unreported mutation in the alanine-glyoxylate aminotransferase gene. The patient underwent simultaneous kidney liver transplant. The second and third cases, 26 and 28 year old women respectively, were asymptomatic siblings of the first patient, who were diagnosed through screening. The fourth case is a 12 year boy with PH type 1 presenting as nephrolithiasis and rapidly worsening kidney function requiring combined kidney liver kidney transplant. Case 5 is a 6 year old male child with type 2 PH presenting with nephrolithiasis, nephrocalcinosis and normal kidney function. All the patients were born to consanguineous parents. CONCLUSIONS: Due to limited clinical suspicion and inadequate diagnostic resources in certain countries with limited resources, it is possible for PH to go undiagnosed. The manifestations of the disease can range from no noticeable symptoms to severe disease. Interestingly, in some individuals with primary hyperoxaluria, the disease may not exhibit any symptoms until it is triggered by a high intake of dietary oxalate.

Qualitative assessment of the patient experience of primary hyperoxaluria type 1: an observational study.

BACKGROUND: Without effective intervention, primary hyperoxaluria type 1 (PH1) causes oxalate-induced kidney damage, leading to end-stage kidney disease and serious complications throughout the body. Although PH1 carries a heavy burden that impacts quality of life, literature on the experiences of those living with PH1 and caring for patients with PH1 is limited. This study aimed to describe the diagnostic journey in PH1 and characterize patients' and caregivers' self-reported experiences throughout the disease course. METHODS: This was an observational study involving in-depth, semi-structured telephone interviews. Dominant trends were assessed using constant comparative analysis to identify themes in interviewees' descriptions of their experiences. Individuals aged ≥ 12 years and caregivers of children aged 6-17 years with genetically confirmed PH1 were eligible. Informed consent/assent and ability to read and speak English were required. RESULTS: Interviewees (16 patients, 12 caregivers) reported a prolonged diagnostic journey due to low disease awareness, among other factors. Upon diagnosis, PH1 was frequently symptomatic, typically involving kidney stone-related symptoms but also potentially symptoms arising beyond the kidneys. PH1 most commonly led to worry and social impairment in adolescents, impaired physical function in adults, and a range of impacts on caregivers. In late-stage disease, dialysis was the most burdensome aspect of living with PH1 (due to time requirements, limitations from living with a catheter, etc.), and this burden was exacerbated by the COVID-19 pandemic. Benefits desired from PH1 management included reductions in laboratory measures of oxalate burden, kidney stone and urination frequency, and oxalate-related skin ulcers. CONCLUSIONS: PH1 greatly impacts patients' and caregivers' lives, primarily due to burdensome disease manifestations and associated emotional, physical, and practical impacts, as well as disease management challenges - particularly those related to dialysis in late-stage disease.