Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. RESULTS: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients. CONCLUSIONS: Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).

The Evolving Role of Genetic Testing in Monogenic Kidney Stone Disease: Spotlight on Primary Hyperoxaluria.

PURPOSE: Multiple factors are thought to give rise to common, recurrent kidney stone disease, but for monogenic stone disorders a firm diagnosis is possible through genetic testing. The autosomal recessive primary hyperoxalurias (PH) are rare forms of monogenic kidney stone disease. All 3 types of PH are caused by inborn errors of glyoxylate metabolism in the liver, leading to hepatic oxalate overproduction and excessive renal urinary oxalate excretion. These conditions are characterized by kidney stones, nephrocalcinosis, progressive chronic kidney disease, and kidney failure. Systemic oxalosis, the extra-renal deposition of oxalate resulting in severe morbidity and mortality, occurs in chronic kidney disease when oxalate clearance by the kidneys declines. Novel small interfering RNA-based therapeutics targeting the liver to reduce urinary oxalate excretion have been approved, introducing precision medicine to treat primary hyperoxaluria type 1. The goal of this narrative review is to address the benefits and practicalities of genetic testing for suspected monogenic kidney stone disease and the critical roles of a multidisciplinary team. MATERIALS AND METHODS: We collated our procedures, education, training, and workflows to help other clinicians integrate genetic assessment into their diagnostic routines. RESULTS: In our experience, increased access to genetic testing facilitates early detection of PH and other monogenic causes of kidney stone disease so that individualized care can be instituted promptly. CONCLUSIONS: Alongside biochemical assessments, more widespread genetic testing may ensure more timely diagnoses so that patients with suspected monogenic kidney stone disease gain access to an expanded range of services and enrollment in clinical trials and registries.

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.

Diagnosis and management of primary hyperoxalurias: best practices.

The primary hyperoxalurias (PH 1, 2, and 3) are rare autosomal recessive disorders of glyoxylate metabolism resulting in hepatic overproduction of oxalate. Clinical presentations that should prompt consideration of PH include kidney stones, nephrocalcinosis, and kidney failure of unknown etiology, especially with echogenic kidneys on ultrasound. PH1 is the most common and severe of the primary hyperoxalurias with a high incidence of kidney failure as early as infancy. Until the recent availability of a novel RNA interference (RNAi) agent, PH care was largely supportive of eventual need for kidney/liver transplantation in PH1 and PH2. Together with the Oxalosis and Hyperoxaluria Foundation, the authors developed a diagnostic algorithm for PH1 and in this report outline best clinical practices related to its early diagnosis, supportive treatment, and long-term management, including the use of the novel RNAi. PH1-focused approaches to dialysis and kidney/liver transplantation for PH patients with progression to chronic kidney disease/kidney failure and systemic oxalosis are suggested. Therapeutic advances for this devastating disease heighten the importance of early diagnosis and informed treatment.

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.

Recurrent symptomatic urolithiasis in a patient with cystic fibrosis.

A 6-month-old girl, previously diagnosed with cystic fibrosis (CF), was admitted to hospital for nephrolithiasis. Her parents were first-degree cousins. The patient underwent endoscopic stone management. Despite no family history of stones and medical treatment with potassium citrate, the patient developed recurrent renal stones and atypical urinary tract infections during follow-up. Basic investigations were all normal. Due to consanguinity and early presentation of nephrolithiasis, metabolic causes such as cystinuria and hyperoxaluria were considered. Cystinuria was excluded due to normal cystine levels. High urinary oxalate excretion was found as expected due to absorptive (secondary) hyperoxaluria in CF patients. An early stone burden in the patient with a history of medical treatment and consanguinity led us to perform a genetic testing. Genetic testing revealed a missense homozygous variant in exon 1 of the AGXT gene. The patient was diagnosed with primary hyperoxaluria type 1. Two rare life-threatening genetic diseases were found together in the same child.

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.

[Clinical analysis of seven cases of primary hyperoxaluria type 1].

We retrospectively analyzed the clinical data of seven patients (four men and three women) with primary hyperoxaluria (PH) type 1 (PH1) in the Department of Nephrology of Zhongda Hospital, Southeast University from January 2018 to October 2023. The mean age at disease onset was 32.1 (range: 26-42) years. The mean age at diagnosis was 40.6 (range: 28-51) years. All patients initially had kidney stones, and three patients were found to have renal insufficiency at the time of disease onset. Among them, two patients underwent hemodialysis immediately. Symptoms at the first visit included bone pain (n=7), joint pain or deformity (n=5), fatigue (n=5), hypotension (n=3), and subcutaneous nodules (n=2). Four patients had a family history of PH. All patients had varying degrees of anemia (60-114 g/L), significant hypoalbuminemia (16.5-32.1 g/L), and hypercoagulable state (D-dimer: 2 230-12 781 µg/L). Seven patients received maintenance hemodialysis; their mean age was 37.7 (range: 26-50) years. The mean duration from disease onset to hemodialysis was 5.6 (range: 0-20) years. Five patients repeatedly experienced dialysis access dysfunction. Three patients underwent kidney transplantation before a diagnosis was made, and all transplanted kidneys lost function due to oxalate deposition. The mean follow-up duration was 14.43 (range: 4-38) months. Unfortunately, one patient died. All seven patients underwent computed tomography of the abdomen. All patients suffered skeletal abnormalities, bilateral nephrolithiasis, and nephrocalcinosis. Six patients carried AGXT gene mutations, including four compound heterozygous mutations and two pure homozygous mutations.The mutation sites included: c.823-824dup.AG (p.S275Rfs*38)(exon 8), c.815-816ins.GA (p.S275Rfs*38)(exon 8), c.595G>A (p.G199S) (exon 5), c.32C>G (p.P11R) (exon 1), and c.638C>T (p.A213V)(exon 6). According to the American College of Medical Genetics and Genomics guidelines, two loci were identified as likely pathogenic variants, seven were identified as pathogenic variants, and one locus was identified as having uncertain significance. In addition, patients 1 and 4 underwent skin biopsy, patient 2 underwent renal transplant biopsy, and patient 3 underwent bone marrow biopsy. Interestingly, significant oxalate deposition was found in the tissues. Therefore, PH1 is a rare autosomal recessive inherited disease. This study not only enhanced the understanding of the clinical characteristics of PH1 patients but also had great significance in early diagnosis and treatment of the disease.

Infant primary hyperoxaluria type 1: A case report and literature review. / å©´å„¿åŽŸå‘æ€§é«˜è‰é ¸å°¿ç—‡1型1ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Primary hyperoxaluria (PH) is a rare autosomal recessive disorder, with PH type 1 (PH1) being the most common. It is primarily characterized by recurrent renal calculi, renal calcification, and can lead to acute renal failure. In infants, PH1 often results in early end-stage renal disease (ESRD) with a high mortality rate. This paper reports a case of an infant with acute renal failure in the Second Hospital of Shandong University who was diagnosed as PH1 using whole-exome sequencing, revealing a homozygous mutation in the AGXT gene (c.596-2A>G), which is reported here for the first time in the Chinese population. Previous literature indicates that urinary oxalate levels and stone composition can suggest PH1, with the gold standard for diagnosis being liver biopsy combined with alanine-glyoxylate aminotransferase (AGT) enzyme activity assessment. However, due to its convenience, AGXT gene sequencing has increasingly become the preferred diagnostic method. Conservative treatments for PH1 include adequate fluid intake, citrate, vitamin B6, and continuous renal replacement therapy, while liver transplantation is the only curative treatment. Infants with unexplained acute renal failure should be evaluated for PH1, with early detection of the level of urine oxalate and screening for genetic testing recommended.

Characterization of Stone Events in Patients With Type 3 Primary Hyperoxaluria.

PURPOSE: Hallmarks of primary hyperoxaluria type 3 are nephrolithiasis and hyperoxaluria. However, little is known about factors influencing stone formation in this disease. We characterized stone events and examined associations with urine parameters and kidney function in a primary hyperoxaluria type 3 population. MATERIALS AND METHODS: We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry. RESULTS: Kidney stones occurred in 65/70 primary hyperoxaluria type 3 patients (93%). Among the 49 patients with imaging available, the median (IQR) number of stones was 4 (2, 5), with largest stone 7 mm (4, 10) at first imaging. Clinical stone events occurred in 62/70 (89%) with median number of events per patient 3 (2, 6; range 1-49). Age at first stone event was 3 years (0.99, 8.7). Lifetime stone event rate was 0.19 events/year (0.12, 0.38) during follow-up of 10.7 (4.2, 26.3) years. Among 326 total clinical stone events, 139 (42.6%) required surgical intervention. High stone event rates persisted for most patients through the sixth decade of life. Analysis was available for 55 stones: pure calcium oxalate accounted for 69%, with mixed calcium oxalate and phosphate in 22%. Higher calcium oxalate supersaturation was associated with increased lifetime stone event rate after adjusting for age at first event (IRR [95%CI] 1.23 [1.16, 1.32]; P < .001). By the fourth decade, estimated glomerular filtration rate was lower in primary hyperoxaluria type 3 patients than the general population. CONCLUSIONS: Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.

Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.

RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

Stiripentol and Lumasiran as a Rescue Therapy for Oxalate Nephropathy Recurrence After Kidney Transplantation in an Adult Patient With Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 is a rare cause of kidney failure. Stiripentol, an inhibitor of lactate dehydrogenase A, and lumasiran, a small interfering RNA targeting glycolate oxidase, have been proposed as therapeutic options, but clinical data are scarce, especially in adults and transplanted patients. We describe the case of a 51-year-old patient with a biopsy-proven recurrence of oxalate nephropathy after a kidney-only transplantation. He received stiripentol and lumasiran without adverse events. Fourteen months after transplantation, graft function, serum, and urinary oxalate levels have remained stable, and kidney biopsy showed a complete regression of oxalate crystals. Further studies are needed to assess whether this strategy is effective and could replace liver-kidney transplantation.

Efficacy and safety of lumasiran for infants and young children with primary hyperoxaluria type 1: 12-month analysis of the phase 3 ILLUMINATE-B trial.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018-004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here. METHODS: Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7-20.5) months). RESULTS: Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)). CONCLUSIONS: Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical and molecular characterization of a large primary hyperoxaluria cohort from Saudi Arabia: a retrospective study.

BACKGROUND: Primary hyperoxalurias (PHs) constitute rare disorders resulting in abnormal glyoxalate metabolism. PH-associated phenotypes range from progressive nephrocalcinosis and/or recurrent urolithiasis to early kidney failure. METHODS: A retrospective study was conducted for patients with confirmed PH diagnoses from three tertiary centers in Saudi Arabia. Detailed clinical molecular diagnosis was performed for 25 affected individuals. Whole exome sequencing (WES)-based molecular diagnosis was performed for all affected individuals. RESULTS: The male:female ratio was 52% male (n = 13) and 48% female (n = 12), and consanguinity was present in 88%. Nephrolithiasis and/or nephrocalcinosis were present in all patients. Kidney stones were present in 72%, nephrocalcinosis in 60%, hematuria in 32%, proteinuria in 16%, abdominal pain in 36%, developmental delay in 8%, and chronic kidney disease stage 5 (CKD stage 5) was observed in 28% of the patients. The most common PH disorder was type I caused by variants in the AGXT gene, accounting for 56%. The GRHPR gene variants were identified in 4 patients, 16% of the total cases. Seven patients did not reveal any associated variants. Missense variants were the most commonly observed variants (48%), followed by frame-shift duplication variants (28%). CONCLUSIONS: Characterization of the genetic and clinical aspects of PH in this unique population provides direction for improved patient management and further research. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-term outcomes after pre-emptive liver transplantation in primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by the liver defect of oxalate metabolism, which leads to kidney failure and systemic manifestations. Until recently, liver transplantation was the only definitive treatment. The timing of liver transplantation can be early, while kidney function is still normal (pre-emptive liver transplantation-PLT), or when the patient reaches stage 5 chronic kidney disease (CKD) and needs combined liver-kidney transplantation. We aimed to determine the long-term kidney outcomes of PLT in PH1 patients. METHODS: A retrospective single-center study of PH1 patients who were followed in our center between 1997 and 2017. We compared the kidney outcomes of patients who underwent PLT to those who presented with preserved kidney function and did not undergo PLT. RESULTS: Out of 36 PH1 patients, 18 patients were eligible for PLT (eGFR > 40 mL/min/1.73 m2 at the time of diagnosis). Seven patients underwent PLT (PLT group), while 11 continued conservative treatments (PLTn group). In the PLT group, the median eGFR at the time of PLT and at the end of the follow-up period (14-20 years) was 72 (range 50-89) and 104 (range 86-108) mL/min/1.73 m2, respectively, and no patient died or reached stage 5 CKD. In the PLTn group, eight patients (72.7%) reached stage 5 CKD (median time to kidney replacement therapy was 11 years), and two patients died from disease complications (18.2%). CONCLUSIONS: Pre-emptive liver transplantation preserved kidney function in patients with PH1 in our cohort. Early intervention can prevent kidney failure and systemic oxalosis in PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.

The retinal phenotype in primary hyperoxaluria type 2 and 3.

BACKGROUND: The primary hyperoxalurias (PH1-3) are rare inherited disorders of the glyoxylate metabolism characterized by endogenous overproduction of oxalate. As oxalate cannot be metabolized by humans, oxalate deposits may affect various organs, primarily the kidneys, bones, heart, and eyes. Vision loss induced by severe retinal deposits is commonly seen in infantile PH1; less frequently and milder retinal alterations are found in non-infantile PH1. Retinal disease has not systematically been investigated in patients with PH2 and PH3. METHODS: A comprehensive ophthalmic examination was performed in 19 genetically confirmed PH2 (n = 7) and PH3 (n = 12) patients (median age 11 years, range 3-59). RESULTS: Median best corrected visual acuity was 20/20. In 18 patients, no retinal oxalate deposits were found. A 30-year-old male with PH2 on maintenance hemodialysis with plasma oxalate (Pox) elevation (> 100 µmol/l; normal < 7.4) demonstrated bilateral drusen-like, hyperreflective deposits which were interpreted as crystallized oxalate. Two siblings of consanguineous parents with PH2 presented with retinal degeneration and vision loss; exome-wide analysis identified a second monogenic disease, NR2E3-associated retinal dystrophy. CONCLUSIONS: Retinal disease manifestation in PH2 and PH3 is rare but mild changes can occur at least in PH2-associated kidney failure. Decline in kidney function associated with elevated plasma oxalate levels could increase the risk of systemic oxalosis. Deep phenotyping combined with genomic profiling is vital to differentiate extrarenal disease in multisystem disorders such as PH from independent inherited (retinal) disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Primary hyperoxaluria type 1 in children: clinical and laboratory manifestations and outcome.

BACKGROUND: Primary hyperoxaluria (PH) results from genetic mutations in different genes of glyoxylate metabolism, which cause significant increases in production of oxalate by the liver. This study aimed to report clinical and laboratory manifestations and outcome of PH type 1 in children in our center. METHODS: A single-center observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients admitted from 2018 to 2020, with a diagnosis of hyperoxaluria (urinary oxalate excretion > 45 mg/1.73 m2/day, or > 0.5 mmol/1.73 m2/day). PH type 1 (PH1) diagnosis was established by identification of biallelic pathogenic variants (compound heterozygous or homozygous mutations) in AGXT gene on molecular genetic testing. RESULTS: The study included 100 patients with hyperoxaluria, with slight male dominance (57%), and median age 1.75 years (range, 1 month-14 years). Initial complaint was urolithiasis or nephrocalcinosis in 47%, kidney failure manifestations in 29%, and recurrent urinary tract infection in 24%. AGXT mutations were detected in 40 patients, and 72.5% of PH1 patients had kidney failure at presentation. Neither gender, age nor urinary oxalate excretion in 24 h had statistical significance in distinguishing PH1 from other forms of hyperoxaluria (P-Value > 0.05). Parental consanguinity, family history of kidney stones, bilateral nephrocalcinosis, presence of oxalate crystals in random urine sample, kidney failure and mortality were statistically significantly higher in PH1 (P-values < 0.05). Mortality was 32.5% among PH1 patients, with 4 PH1 patients (10%) on hemodialysis awaiting combined liver-kidney transplantation. CONCLUSION: PH1 is still a grave disease with wide variety of clinical presentations which frequent results in delays in diagnosis, thus kidney failure is still a common presentation. In Syria, we face many challenges in diagnosis of PH, especially PH2 and PH3, and in management, with hopes that diagnosis tools and modern therapies will become available in our country. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children.

PURPOSE: Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. METHODS: This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. RESULTS: All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. CONCLUSION: Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

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

Primary hyperoxaluria (PH) is a group of genetic disorders that result in an increased hepatic production of oxalate. PH type 3 (PH3) is the most recently identified subtype and results from mutations in the mitochondrial 4-hydroxy-2-oxoglutarate aldolase gene (HOGA1). To date, there have been 2 cases of kidney failure reported in PH3 patients. We present a case of a young man with a history of recurrent urinary tract infections and voiding dysfunction who developed kidney failure at 33 years of age. He developed a bladder stone and bilateral staghorn calculi at 12 years of age. Initial metabolic evaluation revealed hyperoxaluria with very low urinary citrate excretion on multiple measurements for which he was placed on oral citrate supplements. Further investigation of the hyperoxaluria was not completed as the patient was lost to follow-up observation until he presented at 29 years of age with chronic kidney disease stage 4 (estimated glomerular filtration rate 24mL/min/1.73m2). Hemodialysis 3 times a week was started at 33 years of age, and subsequent genetic testing revealed a homozygous HOGA1 mutation (C.973G>A p.Gly325Ser) diagnostic of PH3. The patient is currently being evaluated for all treatment options including possible liver/kidney transplantation. All cases of a childhood history of recurrent urinary stone disease with marked hyperoxaluria should prompt genetic testing for the 3 known PH types. Hyperhydration and crystallization inhibitors (citrate) are standard of care, but the role of RNA interference agents for all 3 forms of PH is also under active study.