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.

Advances in the gene therapy of primary hyperoxaluria / 中华泌尿外科杂志

Primary hyperoxaluria (PH) is a rare autosomal recessive hereditary disease, characterized by calcium oxalate kidney stone and nephrocalcinosis caused by defects in enzymes of liver glyoxylate metabolism. Up to now, treatment options for PH are limited. Although medication treatment and liver transplantation can slow down the progression and mitigate the symptoms, the evidence for them turned out to be weak. In recent years, breakthroughs in biotechnology provide novel promising directions for drug development. Small interfering RNA drugs, such as lumasiran and nedosiran, selectively reduce hepatic expression of glycolate oxidase and lactate dehydrogenase respectively, reducing hepatic oxalate production and urinary oxalate levels in PH patients. Gene-editing, such as CRISPR/Cas9, will be a potential treatment method of PH. This review encompasses recent developments in the gene therapy of PH.

Diagnostic Code-Based Screening for Identifying Children with Primary Hyperoxaluria.

PURPOSE: We evaluated the utility of diagnostic codes to screen for patients with primary hyperoxaluria (PH) and evaluate their positive predictive value (PPV) in identifying children with this rare condition in PEDSnet, a clinical research network of pediatric health systems that shares electronic health records data. MATERIALS AND METHODS: We conducted a cross-sectional study of children who received care at 7 PEDSnet institutions from January 2009 through January 2021. We developed and applied screening criteria using diagnostic codes that generated 3 categories of the hypothesized probability of PH. Tier 1 had specific diagnostic codes for PH; tier 2 had codes for hyperoxaluria, oxalate nephropathy, or oxalosis; and tier 3 had a combination of ≥2 codes for disorder of carbohydrate metabolism and ≥1 code for kidney stones. We reviewed the electronic health records of patients with possible PH to confirm PH diagnosis and evaluate the accuracy and timing of diagnostic codes. The PPV of the codes was compared across tiers, time, PH type, and site. RESULTS: We identified 341 patients in the screen; 33 had confirmed PH (9.7%). Tier 1 had the highest proportion of PH; however, the PPV was only 20%. The degree to which an institution accurately represented point of care diagnoses in the data extraction process was predictive of higher PPV. The PPV of diagnostic codes was highest for PH3 (100%) and lowest for PH1 (22.8%). CONCLUSIONS: Diagnostic codes for PH have poor PPV. Findings suggest that one should be careful in research using large databases in which source validation is not possible.

Etiology, urine metabolic risk factors, and urine oxalate patterns in patients with significant hyperoxaluria and recurrent nephrolithiasis.

PURPOSE: American Urology Association guidelines recommend genetic testing for patients with recurrent stones and urine oxalate > 75 mg/day. The goal of this study was to examine the treatment of patients in this category in a large multidisciplinary adult stone clinic. METHODS: Patients were evaluated from a single institution between 2006 and 2019. Those with at least one level of urinary oxalate excretion (uOx) above 75 mg/day were identified. A chart review identified enteric risk factors and genetic testing results. Patients without an identifiable enteric cause were considered idiopathic. RESULTS: A total of 4229 separate 24-h urine collections in 1302 patients were reviewed. At least one measurement of uOx above 75 mg/day was found in 103 (7.9%) patients. Enteric hyperoxaluria (EH) was seen in 28 (27%) and idiopathic hyperoxaluria (IH) in 76 (74%). 20 (71%) patients in the EH group had undergone gastric bypass. The median uOx was significantly higher level in the EH group (121.0 vs. 93.0 mg/day). For the entire cohort, there was a drop in uOx (- 33.8 mg/day) with medical and dietary therapy after a follow-up of 46.6 months. The final oxalate was higher in EH (88.9 vs. 60.1 mg/day). Only one patient had referral for genetic testing and was found to have primary hyperoxaluria type 2. CONCLUSIONS: The most common cause of significant hyperoxaluria in patients with recurrent nephrolithiasis remains idiopathic. Patients with IH have more significant improvement in uOx compared to EH; however, both groups had hyperoxaluria at last follow-up. Rate of genetic testing is low despite guideline recommendations.

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

Objective: To investigate the clinical, imaging and molecular characteristics of primary hyperoxaluria type 1 (PH1) in children and to sum up existing evidence for further understanding the phenotype-genotype correlation of infantile PH1. Methods: This retrospective analysis was based on the medical records of children with PH1 diagnosed by gene test in the Department of Nephrology, Guangzhou Women and Children's Medical Center from June 2016 to May 2019. Targeted exome sequencing was performed on tubular disease-related genes of the probands and Sanger sequencing was conducted to validate suspected pathogenic variants of family members. Logistic regression analysis of NC and CCr was adopted to show the relation between NC and renal function. The literature review was conducted, and the clinical, imaging and molecular biogenetic characteristics of the disease were analyzed and summarized. Results: A total of 7 children from 6 families were enrolled. The median age of onset was 5 months. The median age of diagnosis was 8 months. Five cases had progressed to end-stage renal disease (ESRD), one case had chronic kidney disease (CKD) stage 1, and the other one had CKD stage 2. Four cases died, one case maintained on hemodialysis, and the other two non-dialysis cases were followed up. Among the 7 cases, 4 patients had infantile PH1, 1 patient had child and adolescent type, 1 patient had family type and the other one had unknown classification. There were two siblings (the younger brother had uremia and the sister had normal renal function) who had the delayed diagnosis for 5 and 3 years respectively. All patients in this cohort had proteinuria and microscopic hematuria, but no patients had gross hematuria. Three cases had hypercalciuria. Comprehensive diagnostic imaging evaluation include CT scan, MR scan, radiography and ultrasound led to the diagnosis of nephrocalcinosis (NC) in 5 cases, including 4 cases of simple NL and 1 case of NC with nephrolithiasis (NL), 1 case of multiple NL and 1 case of microcrystal deposition in renal medulla. However, only one case of NC was identified by ultrasound, the other 4 cases of NC were identified by radiograph examination. In the logistic regression analysis involving NC and creatinine clearnce rate (CCr), the results showed that NC was an independent risk factor for renal dysfunction (OR 2.5, 95%CI 0.7-1.2, P<0.05). All the 7 cases had AGXT gene variant, including homozygous variant in 4 cases and compound heterozygous variant in 3 cases. A total of 9 variant genotypes were found, and exon 6 variants were found in 4 children. Among them, there were 3 cases with c.679_680delAA. To our knowledge, both c.679_680delAA and c.190A>T in the cohort have not been reported previously. Conclusions: Infantile PH1 is the most common type of PH1 in children, which progresses rapidly or even begins with renal failure, with poor prognosis. It is also highly heterogeneous in phenotype and genotype. NC is an independent risk factor leading to renal failure. Radiograph examination showed high specificity for the diagnosis of NC. At present, the misdiagnosis and delayed diagnosis of PH1 are still common in China. It is of great significance to carry out quantitative determination of uric oxalate in order to reduce the misdiagnosis rate and enhance follow-up technologies for evaluating the therapeutic effect.

Clinical analysis of seven cases with primary hyperoxaluria type 1 in children / 中华儿科杂志

Objective@#To investigate the clinical, imaging and molecular characteristics of primary hyperoxaluria type 1 (PH1) in children and to sum up existing evidence for further understanding the phenotype-genotype correlation of infantile PH1.@*Methods@#This retrospective analysis was based on the medical records of children with PH1 diagnosed by gene test in the Department of Nephrology, Guangzhou Women and Children′s Medical Center from June 2016 to May 2019. Targeted exome sequencing was performed on tubular disease-related genes of the probands and Sanger sequencing was conducted to validate suspected pathogenic variants of family members. Logistic regression analysis of NC and CCr was adopted to show the relation between NC and renal function. The literature review was conducted, and the clinical, imaging and molecular biogenetic characteristics of the disease were analyzed and summarized.@*Results@#A total of 7 children from 6 families were enrolled. The median age of onset was 5 months. The median age of diagnosis was 8 months. Five cases had progressed to end-stage renal disease (ESRD), one case had chronic kidney disease (CKD) stage 1, and the other one had CKD stage 2. Four cases died, one case maintained on hemodialysis, and the other two non-dialysis cases were followed up. Among the 7 cases, 4 patients had infantile PH1, 1 patient had child and adolescent type, 1 patient had family type and the other one had unknown classification. There were two siblings (the younger brother had uremia and the sister had normal renal function) who had the delayed diagnosis for 5 and 3 years respectively. All patients in this cohort had proteinuria and microscopic hematuria, but no patients had gross hematuria. Three cases had hypercalciuria. Comprehensive diagnostic imaging evaluation include CT scan, MR scan, radiography and ultrasound led to the diagnosis of nephrocalcinosis (NC) in 5 cases, including 4 cases of simple NL and 1 case of NC with nephrolithiasis (NL), 1 case of multiple NL and 1 case of microcrystal deposition in renal medulla. However, only one case of NC was identified by ultrasound, the other 4 cases of NC were identified by radiograph examination. In the logistic regression analysis involving NC and creatinine clearnce rate (CCr), the results showed that NC was an independent risk factor for renal dysfunction (OR 2.5, 95%CI 0.7-1.2, P<0.05). All the 7 cases had AGXT gene variant, including homozygous variant in 4 cases and compound heterozygous variant in 3 cases. A total of 9 variant genotypes were found, and exon 6 variants were found in 4 children. Among them, there were 3 cases with c.679_680delAA. To our knowledge, both c.679_680delAA and c.190A>T in the cohort have not been reported previously.@*Conclusions@#Infantile PH1 is the most common type of PH1 in children, which progresses rapidly or even begins with renal failure, with poor prognosis. It is also highly heterogeneous in phenotype and genotype. NC is an independent risk factor leading to renal failure. Radiograph examination showed high specificity for the diagnosis of NC. At present, the misdiagnosis and delayed diagnosis of PH1 are still common in China. It is of great significance to carry out quantitative determination of uric oxalate in order to reduce the misdiagnosis rate and enhance follow-up technologies for evaluating the therapeutic effect.

Primary hiperoxaluria diagnosed after kidney transplantation: report of 2 cases and literature review / Hiperoxalúria primária diagnosticada após transplante renal: relato de dois casos e revisão da literatura

Abstract Primary hyperoxaluria (PH) is a very rare genetic disorder; it is characterized by total or partial deficiency of the enzymes related to the metabolism of glyoxylate, with an overproduction of calcium oxalate that is deposited in different organs, mainly the kidney, leading to recurrent lithiasis, nephrocalcinosis and end stage renal disease (ESRD). In patients with ESRD that receive kidney transplantation alone, the disease has a relapse of 100%, with graft loss in a high percentage of patients in the first 5 years of transplantation. Three molecular disorders have been described in PH: mutation of the gene alanin glioxalate aminotransferase (AGXT); glyoxalate reductase/hydroxy pyruvate reductase (GRHPR) and 4-OH-2-oxoglutarate aldolase (HOGA1). We present two cases of patients with a history of renal lithiasis who were diagnosed with primary hyperoxaluria in the post-transplant period, manifested by early graft failure, with evidence of calcium oxalate crystals in renal biopsy, hyperoxaluria, hyperoxalemia, and genetic test compatible; they were managed with proper diet, abundant oral liquids, pyridoxine, hydrochlorothiazide and potassium citrate; however, they had slow but progressive deterioration of their grafts function until they reached end-stage chronic renal disease.

Resumo A hiperoxalúria primária (HP) é um distúrbio genético muito raro, caracterizado por deficiência total ou parcial das enzimas relacionadas ao metabolismo do glioxilato, superprodução de oxalato de cálcio que se deposita em vários órgãos (principalmente os rins) resultando em litíase recorrente, nefrocalcinose e doença renal terminal (DRT). Nos pacientes com DRT que recebem transplante renal, a doença apresenta recidiva em 100% dos casos, com perda do enxerto nos primeiros cinco anos após o transplante num elevado percentual de pacientes. Três distúrbios moleculares foram descritos na HP: mutação dos genes da alanina-glioxilato aminotransferase (AGXT), glioxilato redutase/hidroxipiruvato redutase (GRHPR) e 4-OH-2-oxoglutarato aldolase (HOGA1). Apresentamos dois casos de pacientes com histórico de litíase renal diagnosticados com hiperoxalúria primária no período pós-transplante, manifestada na forma de perda precoce do enxerto com evidências de cristais de oxalato de cálcio na biópsia renal, hiperoxalúria, hiperoxalemia e testes genéticos compatíveis. Os pacientes foram tratados com abordagem nutricional, líquidos orais em abundância, piridoxina, hidroclorotiazida e citrato de potássio. Contudo, os pacientes apresentaram deterioração lenta e gradual da função do enxerto e evoluíram para doença renal terminal.

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

BACKGROUND AND OBJECTIVES: Overproduction of oxalate in patients with primary hyperoxaluria (PH) leads to calcium oxalate deposition in the kidney and ESRD in a substantial number of cases. However, the key determinants for renal outcome remain unclear. Thus, we performed a retrospective analysis to identify predictors for renal outcome among patients with PH participating in the Rare Kidney Stone Consortium (RKSC) PH Registry. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We characterized clinical and laboratory features of patients enrolled in the RKSC PH Registry. We assessed correlation between urinary measures and eGFR at diagnosis by Spearman rank correlation and estimated renal survival using the Kaplan-Meier method. We determined factors associated with renal survival by Cox proportional hazard models. RESULTS: Of 409 patients enrolled in the RKSC Registry as of March 2014, we excluded 112 patients who had ESRD at PH diagnosis from analysis. Among the remaining 297 patients, 65% had PH type 1, 12% had type 2, 13% had type 3, and 11% had unclassified PH. Median (25th, 75th percentile) age at PH diagnosis was 8.1 (4.0, 18.2) years with an eGFR of 73.0 (56.4, 97.5) ml/min per 1.73 m(2) and urinary oxalate excretion rate of 1.64 (1.11, 2.44) mmol/1.73 m(2) per 24 hours. During a median follow-up of 3.9 (1.0, 12.8) years, 59 (20%) patients developed ESRD. Urinary oxalate excretion at diagnosis stratified by quartile was strongly associated with incident ESRD (hazard ratio [HR], 3.4; 95% confidence interval [95% CI], 1.4 to 7.9). During follow-up there was a significant association between urinary oxalate quartile (Q) and incident ESRD (Q4 versus Q1: HR, 3.3; 95% CI, 1.2 to 9.3). This association remained even when adjusted for sex, age, and baseline eGFR (HR, 4.2; 95% CI, 1.6 to 10.8). CONCLUSIONS: Among patients with PH, higher urinary oxalate excretion is predictive of poor renal outcome.

Analysis of mutant genes in a primary hyperoxaluria type Ⅲ family / 中华肾脏病杂志

Objective To describe the clinical characteristics of one child with primary hyperoxaluria types Ⅲ, and to analyze the potential mutant genes in his family.Methods AGXT, GRHPR and HOGA1 genes were analyzed by direct sequencing analysis in this family.One hundred unrelated healthy subjects were also analyzed as controls.Results The child had early onset of symptoms (0.8 year).His principal clinical manifestation included nephrolithiasis and obstructive nephropathy, however his nephrocalcinosis was mild.And he presented high urine oxalate, high urine calcium, and lower citrate levels.Two novel heterozygous mutations in HOGA1 were identified (compound heterozygous), one mutation was a 2-bp substitution at the last position in exon 6 and the first position of intron 6 respectively (c.834_834 + 1GG ＞ TT);another was a guanine to adenine substitution of the last nucleotide of exon 6 (c.834G ＞ A).Both of these variants found in this study probably acted as splicing mutations.Direct sequencing analysis failed to find these mutations in 100 unrelated healthy subjects.In addition, a SNP (c.715G ＞ A, p.V239I) was found in this family.There were no mutations detected in AGXT and GRHPR.Conclusions Two novel mutations are identified probably in association with PH Ⅲ.This is the first description and investigation on mutant gene analysis of PHⅢ in Asia.

Analysis of AGXT gene mutation in a primary hyperoxaluria type Ⅰ family / 中华肾脏病杂志

Objective To describe the clinical characteristics,and to analyze the AGXT gene mutation in three siblings with primary hyperoxaluria type I (PHI).Methods AGXT gene mutation was analyzed by direct sequencing analysis in this family,and the minor allele status was also tested.One hundred unrelated healthy subjects were also analyzed as controls.Results Three mutations in AGXT were identified in each of three patients including two novel heterozygous missense mutations and one previously reported variant.One mutation was a methionine to leucine substitution at position 49 (p.M49L,c.145A ＞ C) in exon 1,one was an asparagine to isoleucine transition at codon 72 (p.N72I,c.215A ＞ T) in exon 2,and another was a heterozygous nonsense mutation at codon 333 (p.R333*).Both p.M49L and p.R333* occured in cis configuration with the minor allele IVS1 +74 bp.Conclusions Two novel mutations are identified probably in association with PHI,however their pathogenicity and potential molecular mechanisms should be explored by further investigations.This is the first investigation on mutant gene analysis of PHI in China.

Hiperoxaluria primaria en tres hermanos / Primary hyperoxaluria in three brothers

La hiperoxaluria es responsable de 2%-20% de las causas metabólicas de litiasis en niños y adolescentes. Esta puede ser secundaria o primaria(HP), en este último caso es tipo I o tipo II, de herencia autosómica recesiva. El objetivo es analizar diagnóstico y evolución en dos hermanos con HP tipo I y un tercero con alta probabilidad. El primer caso presentó a los 9 años un cólico nefrítico con litiasis múltiples bilaterales y una IRA leve. Presentaba hiperoxaluria de 214 mg/1,73 m2. Se descartaron causas secundarias. El estudio genético demostró dos copias de la mutación IIe244Thr. Los otros dos pacientes se presentaron en forma similar, a edades de 8 y 17 años. La piridoxina a altas dosis descendió los niveles de oxaluria como está descrito en un tercio de los casos. El tiempo de evolución es 7,3 y 1 año respectivamente. Persisten actualmente con litiasis bilaterales, sin nefrocalcinosis ni alteraciones del medio interno. La severidad de la HP tipo I es variable, hay formas de presentación temprana con litiasis recurrente y falla renal crónica en la infancia o en la adolescencia; otras de inicio tardío en edad adulta. Se trata de una enfermedad grave, progresiva, cuyo diagnóstico temprano con estudio metabólico completo puede mejorar el pronóstico,fundamentalmente en aquellos que responden a la piridoxina. El manejo de la litiasis y sus complicaciones es fundamental para evitar la IRC. Cuando ésta se desarrolla, la diálisis agresiva y el trasplante hepatorrenal son las opciones terapéuticas. Es el primer informe de casos confirmados de hiperoxaluria primaria en nuestro país...