Primary Hyperoxaluria Type Research Articles

#3589 OXALATE METABOLISM IN PRIMARY HYPEROXALURIA TYPE 1 TREATED WITH LUMASIRAN IMMEDIATELY AFTER BIRTH: STILL NOT EARLY ENOUGH

Abstract Background and Aims Severe primary hyperoxaluria type 1 (PH1) with rapid onset nephrocalcinosis and renal function loss in early infancy required so far combined liver and kidney transplant. RNA interfering drugs are the new challenge for these children. Here we present the first case of a newborn affected by PH1 treated with RNA-interfering Lumasiran 6 hours after birth. Method Diagnosis of PH1 (homozygous mutation AGXT c.731T>C9 [p.Ile244Thr]) was done at 11 weeks of pregnancy on chorionic villus due to family history. Parents are first cousins, both heterozygous carriers of the mutation. Their first child is homozygous, affected by PH1, in dialysis for massive nephrocalcinosis since two months of life, kidney-liver transplanted at 14 months, with multiple comorbidities, severe retinal oxalate deposition, early ischemic stroke and post-transplant lympho-proliferative disease. Mother blood Oxalate, Glycolate and Urinary Oxalate during pregnancy proved normal (3 umol/L and 4 umol/L; 35 umol/mmol). Fetal morphology at ultrasound was normal, showing a male fetus large for gestational age, due to gestational diabetes, and polyhydramnios. At 37w cesarean section was performed. Birth weight 4120 g; Length 49.9 cm (99° centile for gestational age). Apgar score 9/9. Cord blood and amniotic fluid were obtained for Oxalate dosage and Sanger sequencing for diagnosis confirmation. Umbilical central venous line and bladder catheter were placed for immediate start of infusions and serial sampling. Results PH1 was confirmed due to Homozygous mutation AGXT c.731T>C9 [p.(Ile244Thr)]. Oxalate on cord blood was 15 umol/L (nv <10), on amniotic fluid 55 umol/L (nv 19-71), on first urine 401 umol/mmolCr (nv < 300 umol/mmolCr). Blood Oxalate at 6h of life rose to 32 umol/L, Glycolate to 107 umol/L and urinary Oxalate to 573 umol/mmolCr. Serum Creatinin was normal (0.3 mg/dl). At 6 hours of life the child was treated with Glycolate Oxidase RNAi Lumasiran at the dose 6 mg/kg subcutaneously, in combination with Pyridoxin 10 mg/kg/day. Hyperhydration (240 ml/kg/day) was maintained iv for 16 days in combination with oral water and potassium citrate (500 mg in 500 ml/day) above breast feeding. Blood Oxalate was serially assessed every 48 hrs showing a peak level of 108 umol/l (nv <10) at day 6, higher than the supersaturation level of 60 umol/L, then a gradual decline (65-56-62 umol/L at 10-20-30 days respectively). Lumasiran 6 mg/kd was repeated at 30 and 60 days according to schedule, then at 3 mg/kg every month. After the second dose of Lumasiran a steeper decline of blood Oxalate was observed (31-17 umol/L at 45-60 days respectively) reaching the upper normal limit of 12 umol/L after three doses, at 80 days. Urinary Oxalate in spite of Lumasiran early start rose until a maximum of 4173 umol/mmolCr (nv for age <300 umol/mmolCr) at 13 days and gradually declined to 765 umol/mmolCr at 80 days, after three doses. Blood and urine Glycolate initially paralleled Oxalate then increased after each Lumasiran dose. Renal ultrasound normal at birth, showed only minimal hyperechogenic spots during the first 2 months, then mild bilateral hyperechogenic papillary deposits without signs of nephrocalcinosis/stones. Renal function at 3 months of life is normal (serum Creatinine 0.2 mg/dl); child growth on the higher centiles (7 kg), with no adverse events. Conclusion Blood and urine Oxalate serial analysis in a severe case of PH1 treated immediately after birth show that Glycolate Oxidase inhibition has a latency of at least 15 days, even when no previous deposits are present. In these days extremely high level of urine and blood Oxalate, far higher than supersaturation level, are reached, in spite of normal renal function, hyperhydration, B6 and citrate supplementation. This case confirms that familiar severe forms of PH1 should be treated immediately after birth with Lumasiran in combination with aggressive supportive therapy to avoid irreversible nephrocalcinosis and renal failure. Prenatal treatment of these cases might be considered in future.

#5635 SYSTEMIC OXALOSIS: AN OVERVIEW OF THE FINDINGS AND PREVALENCE IN PRIMARY HYPEROXALURIA

Abstract Background and Aims Systemic oxalosis is a severe co-morbidity that may arise in patients with primary hyperoxaluria type 1 (PH1). It is caused by precipitation of calcium oxalate crystals in organs besides the kidneys, as a result of high endogenous oxalate production. In this study, we aimed to provide an overview of the prevalence, features, screening modalities and factors that play a role in developing systemic oxalosis as cohort studies are currently lacking. Method A retrospective registry study was conducted using data from the OxalEurope registry, one of the largest registries of patients with PH1. All patients with primary hyperoxaluria and data on systemic oxalosis were identified. Data was analyzed using descriptive statistics, Chi-square tests, Mann-Whitney U tests and Kaplan Meier analyses. Results A total of 159 out of 291 (55%) screened PH1 patients were diagnosed with systemic oxalosis. In addition, 110 patients were recorded having no signs of systemic oxalosis at follow-up, however screening was not performed. Sixty-two patients had already developed systemic oxalosis at moment of diagnosis and systemic oxalosis was most often found in patients with ESKD (95%). The eyes, bones and heart are most frequently affected, nevertheless deposits occurred in many organs, as shown by obduction. Fundus photography (n = 16), X-ray (n = 43), and echocardiography (n = 59) are the modalities used most often to screen respectively the eyes, bones and heart. Patients who developed systemic oxalosis had significantly higher upper plasma oxalate levels (median 22 versus 175 umol/L, p<0.001). Furthermore, patients with systemic oxalosis had a significant higher mortality rate compared to patients without systemic oxalosis (48 out of 142 versus 10 out of 212, p<0.001), which difference persisted after correcting for ESKD (p<0.001). Kaplan Meier analysis (Figure 1) showed that pediatric patients with ESKD tended to developed systemic oxalosis more frequently than adults (p<0.001). Conclusion This is the first research to systematically study and report systemic oxalosis in patients with primary hyperoxaluria type 1. Systemic oxalosis is prevalent among PH1 patients, especially when ESKD is present, and may lead to significant morbidity and mortality. Patients with systemic oxalosis have a higher mortality rate and pediatric patients may develop systemic oxalosis more frequently than adults. Given the high incidence and possible implications, we would like to make an appeal on screening all patients with systemic oxalosis. Future research should focus on reliable screening modalities for early signs of systemic oxalosis.

#3320 GENETIC TESTING FOR MOLECULAR DIAGNOSIS OF NEPHROLITHIASIS AND NEPHROCALCINOSIS IN ADULT PATIENTS: A SINGLE-CENTER COHORT

Abstract Background and Aims Hereditary factors represent an important cause of nephrolithiasis which will generate stone disease in adult. Molecular analysis in patients with nephrolithiasis (NL) and/or nephrocalcinosis (NC) for a genetic mutation has become more accessible and the benefits are highlighted by an increasing number of publications. The aim of the paper was to study genetic screening for 36 NL and/or NC patients in order to identify the cases that can be confirmed by mutations in known kidney stone genes. Method Between 2020–2022 we included 35 adult patients with NL/NC with onset on pediatric age or in young adults, plus one of the following criteria: family history for NL/NC, indicative phenotype, recurrent NL. All the patients were diagnosed with NL and/or NC by ultrasound or computed tomography scan. Inform consent was signed and dated before blood samples and we performed genetic testing using nephrolithiasis panel (that include 45 genes) from 2 laboratories. In addition, we performed clinical assessment in a multidisciplinary team, underwent metabolic assessment, and caring out the genealogical tree. Results The study included 18 females and 17 males. The mean age of studied patients was 34.9 ± 10.3 years (range 18 – 54 years), although mean age of NL/NC diagnosis was 19.4 ± 12.0 years (range 0.5 – 34 years). 29 patients presented NL of any type, 12 patients presented both NL and NC, and 3 patients isolated NC. All the patients presented positive family history of NL/NC, 17 (48.5%) patients had pediatric age of onset, 17 (48.5%) patients presented indicative phenotype and 19 (54.2%) recurrent stone disease. Causative monogenic mutations were detected in 25 of 35 NL/NC. We identified 20 deleterious variants in 12 out of 45 analyzed genes. Genetic testing was positive with a definite diagnosis (had pathogenic variant) in 17 (48.6%) of cases, while 3 (8.6%) patients presented likely pathogenic variants, and 5 (14.3%) patients had variants of uncertain significance (VUS). In our cohort, the most common cause of kidney stone disease was cystine nephrolithiasis in 8 (22.8%) patients, followed by hereditary distal renal tubular acidosis in 4 patients, Dent disease in 3 patients, primary hyperoxaluria type 1 in 2 patients, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis in 2 patients. Other causes of kidney stone disease included: renal hypouricemia type 1, hereditary hypophosphatemic rickets with hypercalciuria, primary mitochondrial disorders, autosomal dominant familial idiopathic hypercalciuria, Bartter syndrome type 3, and autosomal dominant tubulo-interstitial disease with hyperuricemia. Pathogenic mutations were detected in the following 5 dominant disease genes: SLC7A9 (4 patients), SLC4A1 (3 patients), ADCY10 (1 patient), HNF1B (2 patients), POLG (1 patient). Also, we identified pathogenic mutations in the following 7 recessive disease genes: CLCN5 (3 patients), AGXT (2 patients), CLDN16 (2 patients), SLC3A1 (3 patients), SLC34A3 (1 patient), WDR72 (1 patient), CLCNKB (1 patient). The mean eGFR for the study group was 71.2 ± 37.6 ml/min/1.72 m2. Seventeen patients presented eGFR < 60 ml/min/1.73 m2: seven patients CKD stage 3, four patients CKD stage 4, two patients CKD stage 5, and two patients were with renal replacement therapy. Conclusion Genetic kidney stone disease is an underdiagnosed condition. Although 48.5% of the patients had NL/NC onset on pediatric age, the molecular diagnosis was performed in adulthood, and, for some of them, when they suffer of advanced kidney disease. In our cohort, genetic testing had a high rate of positive molecular diagnosis of NL/NC due to selection criteria. Five of our patients presented VUS, but with disease-specific phenotype. We emphasize the importance of reporting these cases to generate additional evidence that could allow the reclassification of these variants. We conclude that the molecular diagnosis improves patient management, prevent or delay chronic kidney disease, offer possibility of genetic counseling and an extended screening to the family. Thus, our study showed the potential benefits of genetic testing, especially in high-risk groups for stone disease.

#5036 THE OUTCOME OF LUMASIRAN TREATMENT IN 10 PAEDIATRIC PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1

Abstract Background and Aims In primary hyperoxaluria type 1 (PH 1) a rare enzymatic defect in the liver leads to a hepatic overproduction of oxalate. The resulting hyperoxaluria can cause nephrocalcinosis, urolithiasis and renal failure. Conservative treatment options such as hyperhydration, citrate and pyridoxine aim to slow the progression of the disease with a liver transplant currently being the only curative treatment. Since November 2020 Lumasiran is approved for use in patients with PH 1. Lumasiran reduces the hepatic oxalate production by RNA interference and may hence reduce hyperoxaluria. To date there is limited real world data available on the effectiveness of the treatment with Lumasiran. Method This observational study looked at the outcome of Lumasiran treatment in 10 patients under the age of 18 years with genetically confirmed PH 1. The primary end point was percentage reduction in plasma oxalate in the two patients on haemodialysis and percentage reduction of urinary oxalate excretion in the patients with preserved renal function. Secondary end points were change in nephrocalcinosis, urolithiasis and renal function. The follow up time was 6 months in one patient and 12 months in the other nine patients. Results Four of the patients were girls and the median age at the start of treatment was 5.25 years (range 0.3-17.9 years). One of the two patients on haemodialysis showed a decrease in plasma oxalate which allowed for a reduction of dialysis frequency from 5x/week to 3x/week whilst the other patient's dialysis had to be intensified due to worsening systemic oxalosis. In the patients with preserved renal function the median reduction of urinary oxalate was 71% (range 10–91%) after 6 months and 78% (range 61–86%) after 12 months. Two patients reached values in the age specific normal range (Matos et al.). Lumasiran was discontinued after 4 months in one patient and after 8 months in another one due to treatment failure. An improvement in nephrocalcinosis was seen in three patients and two patients showed a subjective reduction in urolithiasis. Renal function improved slightly in one patient and remained stable in the others. Injection site reactions were the only observed side effects. Conclusion Our data highlights the heterogeneity of the disease and treatment response to Lumasiran. Despite promising data regarding the benefits of Lumasiran 2 of 10 patients did not benefit from Lumasiran injections. Hence, it is imperative to regularly re-evaluate hyperoxaluria during treatment with Lumasiran. Ideally the data should be entered into a registry for PH 1 patients to monitor the effectiveness and side effects of this novel drug not only in the short- but also the long term.

Reduced Electroretinogram Responses in Morphologically Normal Retina in Patients with Primary Hyperoxaluria Type 1.

To describe ocular findings in individuals with primary hyperoxaluria type 1 (PH1), focusing on the correlations between retinal anatomy and retinal function. To characterize the retinal alterations that occur at different disease stages by evaluating individuals with diverse degrees of renal impairment associated with PH1. A cross-sectional study. Patients diagnosed with PH1 based on clinical criteria and genetic testing, treated in the Pediatric Nephrology Unit of the Ruth Children's Hospital, Rambam Health Care Campus, Haifa, Israel between 2013 and2021. The ophthalmological assessment included a slit-lamp biomicroscopy of the anterior and posterior segment or indirect ophthalmoscopy. Electroretinography was employed for assessment of the retinal function, and retinal imaging included spectral-domain OCT and fundus autofluorescence. A systematic evaluation of the disease stage was based on clinical criteria including physical examination, purposeful imaging (X-ray, echocardiography, and US abdomen), and laboratory tests as needed. Anatomical and functional assessment of the retina in patients with PH1, and the relationship between retinal dysfunction and kidney impairment. A total of 16 eyes were examined in the study of 8 children ranging in age from 4 to 19years. Four eyes (25%) showed normal structural and functional retinal findings, 8 eyes (50%) presented functional impairment in the absence of pathological structural findings, and 4 eyes (25%) had advanced retinal damage that manifested as significant morphological and functional impairment. There was no direct relationship between the severity of the renal disease and the severity of the retinal phenotype. Subjects with PH1 present varying severity levels of the retinal phenotype, with possible discrepancy between the clinical retinal morphology and the retinal function noted on electroretinography. These findings raise questions about the molecular basis of the retinal manifestations in PH1. The presence of functional impairment in the absence of evident crystal deposition in the retina suggests that, in addition to oxalate crystal accumulation, other biomolecular processes may play a role in the development of retinopathy.

Quantification of oxalate by novel LC-MS/MS: assay development, validation and application in lumasiran clinical trials.

Background: Measurement of plasma oxalate (POx) is challenging, but critical, for management of patients with primary hyperoxaluria type 1. A novel LC-MS/MS assay was developed, validatedand used to quantify POx in patients with primary hyperoxaluria type 1. Methods: Samples (100μl of plasma in K2EDTA) were spiked with internal standard (13C2-labeled oxalic acid), acidifiedand cleaned by protein precipitation before analysis using anion HPLC-ESI-MS/MS. The assay was validated with a quantitation range of 0.500-50.0μg/ml (5.55-555μmol/l). All parameters successfully met acceptance criteria, including 15% (20% at lower limit of quantification) for accuracy and precision. Conclusion: This assay has advantages over previously published POx quantitation methods, was validated in accordance with regulatory guidelines and accurately determined POx levels in humans.

Kidney cysts in patients with HOGA1 variants.

In an era of increased accessibility to genetic testing, nephrologists may be able to better understand pathophysiologic mechanisms by which their patients develop specific conditions. In this study, we describe clinical and genetic findings of two patients with kidney cysts, who were found to have variants in HOGA1, a mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme associated with primary hyperoxaluria type3 and the development of oxalate-containing kidney stones. We describe possible mechanisms by which mutations in this enzyme could result in the kidney cyst formation seen in our two patients. We propose that patients with mutations in HOGA1 are predisposed to crystal or stone deposition, tubule dilation, and inflammasome activation, which can result in kidney cyst formation.

Lumasiran (Oxlumo)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses lumasiran (Oxlumo), 94.5 mg/0.5 mL lumasiran (as lumasiran sodium), subcutaneous injection.
 Indication: For the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels in pediatric and adult patients.

MP16-08 DISTINGUISHING CHARACTERISTICS OF CHILDREN WITH PRIMARY HYPEROXALURIA TYPE 1 IN PEDSNET

You have accessJournal of UrologyCME1 Apr 2023MP16-08 DISTINGUISHING CHARACTERISTICS OF CHILDREN WITH PRIMARY HYPEROXALURIA TYPE 1 IN PEDSNET Gregory Tasian, Kimberley Dickinson, Julia Schuchard, Grace Park, Nicole Marchesani, Akanksha Mittal, Nathan Cheng, Christina Ching, David Chu, Ryan Walton, Karyn Yonekawa, Caroline Gluck, Kathleen Kan, William DeFoor, Kyle Rove, and Christopher Forrest Gregory TasianGregory Tasian More articles by this author , Kimberley DickinsonKimberley Dickinson More articles by this author , Julia SchuchardJulia Schuchard More articles by this author , Grace ParkGrace Park More articles by this author , Nicole MarchesaniNicole Marchesani More articles by this author , Akanksha MittalAkanksha Mittal More articles by this author , Nathan ChengNathan Cheng More articles by this author , Christina ChingChristina Ching More articles by this author , David ChuDavid Chu More articles by this author , Ryan WaltonRyan Walton More articles by this author , Karyn YonekawaKaryn Yonekawa More articles by this author , Caroline GluckCaroline Gluck More articles by this author , Kathleen KanKathleen Kan More articles by this author , William DeFoorWilliam DeFoor More articles by this author , Kyle RoveKyle Rove More articles by this author , and Christopher ForrestChristopher Forrest More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003236.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Primary hyperoxaluria type 1 (PH1) is an ultra-rare disorder of hepatic overproduction of oxalate that causes early onset kidney stones, chronic kidney disease, and systemic oxalosis. We sought to identify defining clinical characteristics of children with PH1 in order to develop approaches that facilitate its early diagnosis. METHODS: We determined the association between patient-level characteristics of PH1 in a case-control study conducted between January 2009 and August 2021 in PEDSnet, a clinical research network of eight pediatric health systems in the United States. We matched each patient with confirmed PH1 to 4 control patients with kidney stone disease not due to PH1 by sex and PEDSnet site at date of diagnosis (cohort entrance date). We obtained patient characteristics and diagnostic test results occurring before to less than 6 months after cohort entrace from a centralized query of the data pooled from the electronic health records and from manual chart review at each PEDSnet site. Differences in patient characteristics and diagnostic test results between patients were compared using paired tests as appropriate for the distribution of and type of data. RESULTS: The study sample included 37 patients with PH1 and 147 controls. Compared to patients with kidney stone disease not due to PH1, patients with PH1 were younger, were less likely to have immobility, had a higher percentage of stone comprised of calcium oxalate monohydrate, and had a lower eGFR measured within 6 months of cohort entrance (Table 1). There were no statistically significant differences in prevalent diagnosis of failure to thrive, cumulative stone size on ultrasound, nephrocalcinosis on ultrasound or CT, or echocardiography results. CONCLUSIONS: In this study, children with PH1 were characterized by presentation before adolescence, absence of immobility, high percentage of calcium oxalate monohydrate stone composition, and decreased eGFR at diagnosis. If validated in external populations, these consortium of characteristics may enable a strong clinical suspicion for PH1 diagnosis, facilitating confirmatory testing, and facilitating initation of targeted therapeutics. Source of Funding: Alnylam Pharmaceuticals © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e205 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gregory Tasian More articles by this author Kimberley Dickinson More articles by this author Julia Schuchard More articles by this author Grace Park More articles by this author Nicole Marchesani More articles by this author Akanksha Mittal More articles by this author Nathan Cheng More articles by this author Christina Ching More articles by this author David Chu More articles by this author Ryan Walton More articles by this author Karyn Yonekawa More articles by this author Caroline Gluck More articles by this author Kathleen Kan More articles by this author William DeFoor More articles by this author Kyle Rove More articles by this author Christopher Forrest More articles by this author Expand All Advertisement PDF downloadLoading ...

MP10-01 EFFICACY AND SAFETY OF LUMASIRAN IN PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1: 36-MONTH ANALYSIS OF THE ILLUMINATE-A TRIAL

You have accessJournal of UrologyCME1 Apr 2023MP10-01 EFFICACY AND SAFETY OF LUMASIRAN IN PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1: 36-MONTH ANALYSIS OF THE ILLUMINATE-A TRIAL John Lieske, Jeffrey Saland, Jaap Groothoff, Yaacov Frishberg, Hadas Shasha-Lavsky, Daniella Magen, Shabbir Moochhala, Eva Simkova, Martin Coenen, Wesley Hayes, Julien Hogan, Anne-Laure Sellier-Leclerc, Yinggu Bao, John Gansner, and Sally-Anne Hulton John Lieske John Lieske More articles by this author , Jeffrey SalandJeffrey Saland More articles by this author , Jaap GroothoffJaap Groothoff More articles by this author , Yaacov FrishbergYaacov Frishberg More articles by this author , Hadas Shasha-LavskyHadas Shasha-Lavsky More articles by this author , Daniella MagenDaniella Magen More articles by this author , Shabbir MoochhalaShabbir Moochhala More articles by this author , Eva SimkovaEva Simkova More articles by this author , Martin CoenenMartin Coenen More articles by this author , Wesley HayesWesley Hayes More articles by this author , Julien HoganJulien Hogan More articles by this author , Anne-Laure Sellier-LeclercAnne-Laure Sellier-Leclerc More articles by this author , Yinggu BaoYinggu Bao More articles by this author , John GansnerJohn Gansner More articles by this author , and Sally-Anne HultonSally-Anne Hulton More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003225.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by hepatic oxalate overproduction leading to kidney stones and progressive kidney disease. Lumasiran is an RNAi therapeutic approved for the treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate levels in pediatric and adult patients. Here, we report data from the 36-month (M) analysis of ILLUMINATE-A, a Phase 3 trial of lumasiran (NCT03681184). METHODS: ILLUMINATE-A is an ongoing Phase 3 trial in patients age ≥6 years with genetically confirmed PH1 and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. A 6M double-blind, placebo-controlled primary analysis period is followed by an extension period (up to 54M) in which all patients receive lumasiran. RESULTS: Of 39 patients enrolled, 24/26 in the lumasiran/lumasiran group and 13/13 in the placebo/lumasiran group entered and continue in the extension period. Mean 24-hour UOx reduction at M36 relative to baseline was 63% in the lumasiran/lumasiran group and 55% in the placebo/lumasiran group (M30 post–lumasiran initiation). At M36, the proportion of patients achieving 24-hour UOx excretion ≤1.5× upper limit of normal was 76% in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group. Mean baseline-to-M36 reductions in plasma oxalate were 36% and 37% in the lumasiran/lumasiran and placebo/lumasiran groups, respectively. In both groups, eGFR remained stable through M36. Kidney stone event rates decreased from 3.19/person-year during the 12M before consent to 0.70/person-year in the lumasiran/lumasiran group and from 0.54/person-year to 0.39/person-year in the placebo/lumasiran group. Medullary nephrocalcinosis generally remained stable or improved. The most common lumasiran-related adverse events were mild injection-site reactions (36% of patients). CONCLUSIONS: Long-term treatment with lumasiran led to sustained UOx reduction through M36, with an acceptable safety profile in patients with PH1 and encouraging clinical outcomes data. Source of Funding: Alnylam Pharmaceuticals © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e114 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Lieske More articles by this author Jeffrey Saland More articles by this author Jaap Groothoff More articles by this author Yaacov Frishberg More articles by this author Hadas Shasha-Lavsky More articles by this author Daniella Magen More articles by this author Shabbir Moochhala More articles by this author Eva Simkova More articles by this author Martin Coenen More articles by this author Wesley Hayes More articles by this author Julien Hogan More articles by this author Anne-Laure Sellier-Leclerc More articles by this author Yinggu Bao More articles by this author John Gansner More articles by this author Sally-Anne Hulton More articles by this author Expand All Advertisement PDF downloadLoading ...

194 Efficacy and Safety of Lumasiran in Patients with Primary Hyperoxaluria Type 1: 36-Month Analysis of the ILLUMINATE-A Trial

194 Efficacy and Safety of Lumasiran in Patients with Primary Hyperoxaluria Type 1: 36-Month Analysis of the ILLUMINATE-A Trial

Primary Hyperoxaluria Type 1: The First Patient Treated with Lumasiran in Portugal

Primary hyperoxaluria type 1 is a rare genetic disease caused by mutations in AGXT, leading to an excessive hepatic production of oxalate, resulting in urolithiasis, nephrocalcinosis and chronic kidney disease. The authors present the case of a young female with PH1 who is the first patient treated with lumasiran in Portugal, and currently has a follow-up of 18 months.

Long-term outcome after combined or sequential liver and kidney transplantation in children with infantile and juvenile primary hyperoxaluria type 1.

Combined or sequential liver and kidney transplantation (CLKT/SLKT) restores kidney function and corrects the underlying metabolic defect in children with end-stage kidney disease in primary hyperoxaluria type 1 (PH1). However, data on long-term outcome, especially in children with infantile PH1, are rare. All pediatric PH1-patients who underwent CLKT/SLKT at our center were analyzed retrospectively. Eighteen patients (infantile PH1 n = 10, juvenile PH1 n = 8) underwent transplantation (CLKT n = 17, SLKT n = 1) at a median age of 5.4 years (1.5-11.8). Patient survival was 94% after a median follow-up of 9.2 years (6.4-11.0). Liver and kidney survival-rates after 1, 10, and 15 years were 90%, 85%, 85%, and 90%, 75%, 75%, respectively. Age at transplantation was significantly lower in infantile than juvenile PH1 (1.6 years (1.4-2.4) vs. 12.8 years (8.4-14.1), P = 0.003). Median follow-up was 11.0 years (6.8-11.6) in patients with infantile PH1 vs. 6.9 years (5.7-9.9) in juvenile PH1 (P = 0.15). At latest follow-up kidney and/or liver graft loss and/or death showed a tendency to a higher rate in patients with infantile vs. juvenile PH1 (3/10 vs. 1/8, P = 0.59). In conclusion, the overall patient survival and long-term transplant outcome of patients after CLKT/SLKT for PH1 is encouraging. However, results in infantile PH1 tended to be less optimal than in patients with juvenile PH1.

Simple, fast and inexpensive quantification of glycolate in the urine of patients with primary hyperoxaluria type 1

In primary hyperoxaluria type 1 excessive endogenous production of oxalate and glycolate leads to increased urinary excretion of these metabolites. Although genetic testing is the most definitive and preferred diagnostic method, quantification of these metabolites is important for the diagnosis and evaluation of potential therapeutic interventions. Current metabolite quantification methods use laborious, technically highly complex and expensive liquid, gas or ion chromatography tandem mass spectrometry, which are available only in selected laboratories worldwide. Incubation of ortho-aminobenzaldehyde (oABA) with glyoxylate generated from glycolate using recombinant mouse glycolate oxidase (GO) and glycine leads to the formation of a stable dihydroquinazoline double aromatic ring chromophore with specific peak absorption at 440 nm. The urinary limit of detection and estimated limit of quantification derived from eight standard curves were 14.3 and 28.7 µmol glycolate per mmol creatinine, respectively. High concentrations of oxalate, lactate and L-glycerate do not interfere in this assay format. The correlation coefficient between the absorption and an ion chromatography tandem mass spectrometry method is 93% with a p value < 0.00001. The Bland–Altmann plot indicates acceptable agreement between the two methods. The glycolate quantification method using conversion of glycolate via recombinant mouse GO and fusion of oABA and glycine with glyoxylate is fast, simple, robust and inexpensive. Furthermore this method might be readily implemented into routine clinical diagnostic laboratories for glycolate measurements in primary hyperoxaluria type 1.

Plasma oxalate and glycolate concentrations in dialysis patients with and without primary hyperoxaluria type 1.

Plasma oxalate and glycolate concentrations in dialysis patients with and without primary hyperoxaluria type 1.

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

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. We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry. 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. Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.

Primary hyperoxaluria I, II, III types in children (review of literature)

This review presents the latest data on the classification, pathogenesis, clinical and genetic features, and therapy of primary hyperoxaluria types I, II, and III in children with autosomal recessive inheritance. ORPHA portal of orphan diseases presents genes responsible for primary hyperoxaluria type I AGXT (93598); type II and type II GRHPR (93599), type III HOGA1 (93600). Worldwide genetic studies have established the pathogenesis, clinical phenotype and genotype features of primary hyperoxaluria. The pathogenesis of primary hyperoxaluria in children is based on impaired hepatic glyoxylate metabolism. The enzyme AGT catalyzes the conversion of L-alanine and glyoxylate to pyruvate and glycine, with vitamin B6 (pyridoxine) serving as a coenzyme for this reaction. Increased production of endogenous oxalate leads to increased blood oxalate concentrations and urinary oxalate excretion with the formation of renal calcium oxalate crystals and radiopaque concrements (calcium oxalate monohydrate – vevelite, calcium oxalate dihydrate – vedellite). High risk of progression to chronic kidney disease in primary hyperoxaluria in children of types I and II. Systemic oxalosis develops with increasing serum oxalate levels and the formation of calcium oxalate crystals with deposition in many organs and tissues. Therapy for primary hyperoxaluria in children includes: hydration (3l/m2/day) and citrates 100–150 mg/kg/day (potassium citrate 0.3–0.5 mmol/kg/day), pyridoxine at a dose of 5 to 20 mg/kg/day for vitamin B6 sensitive type I primary hyperoxaluria. Administration of oxalobacter formigenes and diet is effective. Combined liver and then kidney transplantation or simultaneous liver and kidney transplantation in patients with type I PH in B6-insensitive and isolated liver transplantation in B6-sensitive variants are performed. Timely molecular genetic testing in children with nephrocalcinosis makes it possible to establish a clinical and genetic diagnosis of type I, II, III PH, to carry out a personalised approach to treatment and to predict future health status.

Glycolate oxidase inhibition by lumasiran varies between patients with primary hyperoxaluria type 1

Glycolate oxidase inhibition by lumasiran varies between patients with primary hyperoxaluria type 1

Lumasiran (Oxlumo)

&#x0D; CADTH recommends that Oxlumo be reimbursed by public drug plans for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients if certain conditions are met.&#x0D; Oxlumo should only be covered to treat those with a genetically confirmed diagnosis of PH1 and whose urine oxalate excretion is not normalized with standard of care therapy (including 3 to 6 months of vitamin B6).&#x0D; Oxlumo should only be reimbursed if its cost is reduced and it is initially prescribed by a nephrologist or metabolic diseases specialist experienced in the diagnosis and management of PH1.&#x0D;

Estimating health state utilities in primary hyperoxaluria type 1: a valuation study

AimsQuantitative data on health state utilities in primary hyperoxaluria type 1 (PH1) are lacking. This study was conducted to estimate utility values in PH1 using 3 standard valuation techniques.Materials and methodsHealth state vignettes were developed with input from expert clinicians to describe different stages of chronic kidney disease (CKD) within the setting of PH1, along with a post-combined liver and kidney transplant (CLKT) health state ≥12 months following transplantation. The utility associated with living in each PH1 health state, as described by the vignettes, was evaluated by members of the UK general public using standard utility assessment techniques, including EQ-5D-5L, Visual Analog Scale, and Time Trade-Off.ResultsA similar pattern across the three valuation methods was observed. Utility values were roughly constant from CKD stage 1–3b and then dropped sharply from these states to CKD stage 4. Decreases in utility in the later stages of CKD (stages 4–5) were followed by a recovery in quality of life in the post-CLKT health state.LimitationsVignettes may not fully capture the burden of living with PH1.ConclusionsThis study serves as an informative source of data on how the burden of PH1 varies across disease stages of CKD and post-CLKT in patients with PH1. The study findings highlight the unique clinical features of PH1 compared with non-PH1-related CKD, such as the need for earlier and more intensive hemodialysis, the risk of systemic oxalosis, and the potential need for CLKT (as opposed to kidney-only transplant). The impact of PH1 on health-related quality of life, which worsens once hemodialysis is required and systemic disease manifestations occur, is captured in this study using quantitative health state utilities. These data provide an understanding of the impact of PH1 on health-related quality of life and will facilitate health economic evaluation of future treatments.