Primary Hyperoxaluria Research Articles

A narrative review of monogenic disorders causing nephrolithiasis and chronic kidney disease.

The incidence and prevalence of genetic diseases associated with chronic kidney disease (CKD) have been increasing over the last decades. To identify the monogenic causes of kidney stone disorders linked to CKD, a comprehensive literature review was conducted to identify monogenic genes causing nephrolithiasis and CKD. Among 41 identifiable monogenic causes of nephrolithiasis the following diseases primary hyperoxaluria familial hypomagnesemia with hypercalciuria and nephrocalcinosis, cystinuria; Dent disease, adenine phosphoribosyltransferase deficiency, Lesch-Nyhan syndrome, and idiopathic Infantile hypercalciuria have been linked to CKD and may progress to end-stage kidney disease (ESKD). Autosomal dominant hypocalcemia and Bartter syndrome (BS) are also hereditary kidney diseases that can cause urolithiasis but are rarely associated with CKD. A few BS type III can be complicated with CKD. A substantial number of kidney stone patients with genetic disorders progress to CKD. Genetic diagnosis should be initiated in all children presenting with kidney stones.

Spinal Cord Compression as the First Presentation of Primary Hyperoxaluria in a Patient With Kidney Failure: A Case Report and Literature Review

Spinal Cord Compression as the First Presentation of Primary Hyperoxaluria in a Patient With Kidney Failure: A Case Report and Literature Review

Primary hyperoxaluria type 3: from infancy to adulthood in a genetically unique cohort.

Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder caused by bi-allelic genetic variants in the 4 hydroxy-2 oxoglutarate aldolase (HOGA-1) gene. We report the natural history of PH3 in a 16-patient cohort, 15 from a unique genetically isolated population. This retrospective single-center study followed PH3 patients between 2003 and 2023 with demographic, clinical, radiographic, genetic, and biochemical parameters. Genetic population screening was performed in four villages to determine carrier frequency and identify couples at risk in a genetically isolated population. Sixteen patients with biallelic (or homozygous) pathogenic variants (PV) in HOGA-1 (c.944_946 del, c.119C > A, c.208C > T) were included in the study, 15 Druze and one Jewish, aged 0-63years at diagnosis (4 adults and 12 pediatric patients). All symptomatic patients had clinical or imaging signs of nephrolithiasis. One developed chronic kidney disease (CKD) stage 5; biopsy showed focal mesangial sclerosis and chronic tubulo-interstitial changes with few oxalate deposits. Two other patients had CKD stage 2 (eGFR 87 and 74mL/min/1.73m2) upon their last visit. The remaining cohort showed preserved kidney function until the latest follow-up. Of 1167 healthy individuals screened, 90 carriers were found, a rate of 1:13 in the genetically unique cohort screened. A high prevalence of PH3 patients was found among a unique cohort, but probably still underdiagnosed due to relatively mild disease course. The carrier rate is high. There is no specific therapy for PH3, but early diagnosis can prevent redundant diagnostic efforts and provide early treatment for kidney stone disease. Even in our homogeneous cohort, kidney stone disease severity and CKD degree were variable, supporting a suspected contribution of yet unknown genetic or environmental factors.

Genetics in nephrology - any news?

While genetic kidney diseases were long regarded as a rare cause of kidney failure, it has been shown in recent years that they account for a relevant proportion of cases. In cohorts of kidney transplant recipients, a monogenic cause is found in up to 30% of cases. Identifying the genetic cause of kidney disease has become much easier thanks to technological advances in DNA sequencing. The focus has now shifted to understanding the significance of the findings and identifying diagnostic gaps. It is still not possible to clarify all CKD cases of unclear aetiology. Besides very effective generic treatments for monogenic kidney disease (e.g., ACE-inhibitor use in Alport Syndrome), increasing knowledge of the pathophysiology of genetic kidney diseases has led to a growing number of targeted therapies. These include the treatment of ADPKD with Tolvaptan, which has now been in use for 10 years. Recently, exciting, and completely new approaches have been added, such as the first siRNA therapies in nephrology for primary hyperoxaluria type 1, the targeted treatment of hyperphagia in Bardet-Biedl syndrome, the therapy of APOL1-associated kidney disease or the use of the HIF-2 antagonist Belzutifan for renal cell carcinoma associated with Von-Hippel-Lindau syndrome. The new possibilities in the treatment of patients with genetic kidney diseases have also clearly revealed deficits in current patient care. Centers of excellence with extensive experience in this area therefore play an important role in improving care. This also applies to the further training of colleagues in the field. In Germany, the National Action Alliance for People with Rare Diseases (NAMSE) and the nationwide establishment of - to date - 36 centers for rare diseases play an important role in this regard.

Oxygen control in bioreactor drives high yield production of functional hiPSC-like hepatocytes for advanced liver disease modelling

Hepatocytes-like cells (HLC) derived from human induced pluripotent stem cells show great promise for cell-based liver therapies and disease modelling. However, their application is currently hindered by the low production yields of existing protocols. We aim to develop a bioprocess able to generate high numbers of HLC. We used stirred-tank bioreactors with a rational control of dissolved oxygen concentration (DO) for the optimization of HLC production as 3D aggregates. We evaluated the impact of controlling DO at physiological levels (4%O2) during hepatic progenitors’ stage on cell proliferation and differentiation efficiency. Whole transcriptome analysis and biochemical assays were performed to provide a detailed characterization of HLC quality attributes. When DO was controlled at 4%O2 during the hepatic progenitors’ stage, cells presented an upregulation of genes associated with hypoxia-inducible factor pathway and a downregulation of oxidative stress genes. This condition promoted higher HLC production (maximum cell concentration: 2 × 106 cell/mL) and improved differentiation efficiencies (80% Albumin-positive cells) when compared to the bioreactor operated under atmospheric oxygen levels (21%O2, 0.6 × 106 cell/mL, 43% Albumin positive cells). These HLC exhibited functional characteristics of hepatocytes: capacity to metabolize drugs, ability to synthesize hepatic metabolites, and inducible cytochrome P450 activity. Bioprocess robustness was confirmed with HLC derived from different donors, including a primary hyperoxaluria type 1 (PH1) patient. The generated PH1.HLC showed metabolic features of PH1 disease with higher secretion of oxalate compared with HLC generated from healthy individuals. This work reports a reproducible bioprocess, that shows the importance of controlling DO at physiological levels to increase HLC production, and the HLC capability to display PH1 disease features.

Lipid nanoparticle-mediated base-editing of the Hao1 gene achieves sustainable primary hyperoxaluria type 1 therapy in rats.

Primary hyperoxaluria type 1 (PH1) is a severe hereditary disease, leading to the accumulation of oxalate in multiple organs, particularly the kidney. Hydroxyacid oxidase 1 (HAO1), a pivotal gene involved in oxalate production, is an approved target for the treatment of PH1. In this study, we demonstrated the discovery of several novel therapeutic sites of the Hao1 gene and the efficient editing of Hao1 c.290-2 A in vivo with lipid nanoparticles (LNP) delivered adenine base editing (ABE) mRNA. A single infusion of LNP-ABE resulted in a near-complete knockout of Hao1 in the liver, leading to the sustainable normalization of urinary oxalate (for at least 6 months) and complete rescue of the patho-physiology in PH1 rats. Additionally, a significant correlation between Hao1 editing efficiency and urinary oxalate levels was observed and over 60% Hao1 editing efficiency was required to achieve the normalization of urinary oxalate in PH1 rats. These findings suggest that the LNP-mediated base-editing of Hao1 c.290-2 A is an efficient and safe approach to PH1 therapy, highlighting its potential utility in clinical settings.

Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria.

Primary hyperoxaluria type 1 is responsible for pediatric kidney failure in 1 to 2% of cases. Novel therapies based on RNA interference are changing the natural history of the disease. However, for those who do progress to kidney failure, and for patients living in countries that cannot afford these expensive therapies, liver-kidney transplantation may remain the only efficient therapy. The aim of the study was to evaluate the outcome of patients with primary hyperoxaluria type 1 who received simultaneous or sequential liver-kidney transplantation. We retrospectively evaluated 10 patients, five of whom received a simultaneous transplantation, and five underwent sequential transplantation, with a median postponement of the kidney transplantation of 8months (range 4-20). Among the patients, 5 were from medium-lowincome countries. Median follow up was 3.2years (range 1.6-11). Median estimated glomerular filtration rate at 6 and 12months was 81.2 (range: 45.7-108.8) and 79.3ml/min/1.73m2 (range 54.7-112.1) in patients who underwent simultaneous transplantation, and 45.7 (range 34.5-86.7) and 38.3ml/min/1.73m2 (range 29.9-77.5) in those with sequential transplantation (p:NS). Biopsies performed at 6 and 12months showed precipitation of calcium oxalate crystals in 7 patients, demonstrating the recurrence of deposition despite the delay between liver and kidney transplantation. No differences in kidney function or in post-transplant renal oxalate precipitation were observed between patients that underwent bilateral nephrectomy and those who did not. As of their most recent follow up, none of the patients has lost their kidney graft. Our study shows that by adapting the transplant strategy to individual cases, patients with primary hyperoxaluria type 1 can be successfully treated.

Can endogenous ethylene glycol production occur in humans? A detailed investigation of adult monozygotic twin sisters

Introduction To the best of our knowledge, clinically significant endogenous ethylene glycol production has never been reported in humans, very seldom reported in other animals or microorganisms, and then only under rare and specific conditions. We describe the detailed investigations we undertook in two adult monozygotic twin sisters to ascertain whether they were producing endogenous ethylene glycol. Methods Two previously healthy monozygotic adult twin sisters presented with recurrent episodes of apparent ethylene glycol poisoning beginning at age 35, requiring chronic hemodialysis to remove ethylene glycol and its metabolites as well as to restore metabolic homeostasis. The sisters denied ingestion or exposure to ethylene glycol. At their request, they were admitted to hospital under strict supervision to exclude surreptitious ingestion of ethylene glycol and to evaluate the need for treatment. Hemodialysis was withheld during this prospective study. Twin A was admitted for 14 days and twin B for 11 days. Serial biochemical analyses were performed in blood and urine. Clinical exome sequencing and mitochondrial deoxyribonucleic acid sequencing were also completed. Results In both twins, ethylene glycol was detected in urine, along with intermittent increases in concentrations of lactate, glycolate, and glycine in blood and/or urine. Blood ethylene glycol concentrations, however, remained <62 mg/L (<1 mmol/L) but became positive soon after discharge. The oxalate concentration remained normal in blood and urine. Plasma and urine amino acid profiles showed intermittent small increases in glycine, serine, taurine, proline, and/or alanine concentrations. Exome sequencing and mitochondrial deoxyribonucleic acid sequencing were non-diagnostic. Neither twin has been admitted with metabolic acidosis nor ethylene glycol poisoning since chronic hemodialysis was started. Twin A developed a calcium oxalate dihydrate lithiasis. Discussion Mitochondrial disease, methylmalonic/propionic/isovaleric aciduria, primary hyperoxaluria, and analyte error were all excluded in these twins, as were obvious common environmental exposures. Conclusion Detailed investigations were performed in adult monozygotic twin sisters to ascertain whether they were producing endogenous ethylene glycol. Alternative explanations were excluded to the very best of our efforts and knowledge. Global metabolomics, gut microbiome analyses, and whole genome sequencing are pending.

Effective Newborn Screening for Type 1 and 3 Primary Hyperoxaluria

IntroductionNewborn Screening programs for a defined set of eligible diseases have been enormously successful, but genomic newborn screening allowing for detection of additional treatable disorders has not been broadly implemented. All three types of primary hyperoxaluria (PH1-3) are rare autosomal recessive diseases caused by distinct defects of glyoxylate metabolism that are diagnosed genetically with certainty. Early diagnosis and treatment are mandatory to avoid renal failure or sequalae associated with persistent hyperoxaluria. MethodsThe prospective pilot study was undertaken within the framework of the German Newborn Screening. DNA samples extracted from dried blood spot cards were screened by multiplex PCR for the two most prevalent mutations: AGXT c.508G>A (PH1) and HOGA1 c.700+5G>T (PH3). Heterozygous AGXT/HOGA1 carriers received repeated spot urine analyses and, in case of persistent hyperoxaluria, complete Sanger sequencing of AGXT and HOGA1 gene, respectively. ResultsBetween March 15th 2022 and June 30th 2023 additional screening for PH1 and PH3 was performed in 77199 out of 222638 newborns included in the regular newborn screening program. No homozygous individuals, but 274 potential carriers for the AGXT mistargeting and 287 potential carriers for the HOGA1 splice variant were identified. Further work up revealed two already symptomatic compound heterozygous infants, one with PH1 (genotype c.508G>A; c.33delC) and one with PH3 (genotype: c.700+5G>T;c.134C>G). A second symptomatic PH1 patient (father of an identified carrier; genotype: c.508G>A;c.508G>A) was uncovered via family history. ConclusionThis pilot study demonstrated the efficacy of a genomic neonatal screening program for primary hyperoxaluria even in relatively small cohorts.

The Secret Ingredient for Isolated Kidney Transplantation with Primary Hyperoxaluria: A Case Report

The Secret Ingredient for Isolated Kidney Transplantation with Primary Hyperoxaluria: A Case Report

Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated disruption of glycolate oxidase

Primary hyperoxaluria type 1 (PH1) is a severe genetic metabolic disorder caused by mutations in the AGXT gene, leading to defects in enzymes crucial for glyoxylate metabolism. PH1 is characterized by severe, potentially life-threatening manifestations due to excessive oxalate accumulation, which leads to calcium oxalate crystal deposits in the kidneys and, ultimately, renal failure and systemic oxalosis. Existing substrate reduction therapies, such as inhibition of liver-specific glycolate oxidase (GO) encoded by HAO1 using siRNA or CRISPR/Cas9 delivered by adeno-associated virus (AAV), either require repeated dosing or have raised safety concerns. To address these limitations, our study employed lipid nanoparticles (LNPs) for CRISPR/Cas9 delivery to rapidly generate a PH1 mouse model and validate the therapeutic efficacy of LNP-CRISPR/Cas9 targeting the Hao1 gene. The LNP-CRISPR/Cas9 system exhibited efficient editing of the Hao1 gene, significantly reducing GO expression and lowering urinary oxalate levels in treated PH1 mice. Notably, these effects persisted for 12 months with no significant off-target effects, liver-induced toxicity, or substantial immune responses, highlighting the approach's safety and specificity. Furthermore, the developed humanized mouse model validated the efficacy of our therapeutic strategy. These findings support LNP-CRISPR/Cas9 targeting HAO1 as a promising and safer alternative for PH1 treatment with a single administration.

Long-Term Efficacy and Safety of Lumasiran in Patients with Primary Hyperoxaluria Type 1: Final Analysis of the ILLUMINATE-A Trial

Long-Term Efficacy and Safety of Lumasiran in Patients with Primary Hyperoxaluria Type 1: Final Analysis of the ILLUMINATE-A Trial

Less Is More: A Case of Isolated Kidney Transplantation with Lumasiran in Primary Hyperoxaluria Type 1

Less Is More: A Case of Isolated Kidney Transplantation with Lumasiran in Primary Hyperoxaluria Type 1

PHYOX3: Long-Term Safety and Efficacy of Nedosiran in Patients with Primary Hyperoxaluria Type 1

PHYOX3: Long-Term Safety and Efficacy of Nedosiran in Patients with Primary Hyperoxaluria Type 1

Development of ABO-101, a Novel Gene Editing Therapy for Primary Hyperoxaluria Type 1

Development of ABO-101, a Novel Gene Editing Therapy for Primary Hyperoxaluria Type 1

Kidney Function and Isolated Kidney Transplant Outcomes in Primary Hyperoxaluria Type 1 Treated with Long-Term Lumasiran

Kidney Function and Isolated Kidney Transplant Outcomes in Primary Hyperoxaluria Type 1 Treated with Long-Term Lumasiran

Burden of Illness of Primary Hyperoxaluria with CKD

Burden of Illness of Primary Hyperoxaluria with CKD

Tracking Selective Internalization and Intracellular Dynamics of Modified Chitosan Polymeric Micelles of Interest in Primary Hyperoxaluria Diseases.

Primary hyperoxalurias (PHs) represent rare diseases associated with disruptions in glyoxylate metabolism within hepatocytes. Impaired glyoxylate detoxification in PH patients results in its accumulation and subsequent conversion into oxalate, a process catalyzed by the hepatic lactate dehydrogenase A enzyme (hLDHA). Targeting this enzyme selectively in the liver using small organic molecules emerges as a potential therapeutic strategy for PH. However, achieving selective hepatic inhibition of hLDHA poses challenges, requiring precise delivery of potential inhibitors into hepatocytes to mitigate adverse effects in other tissues. Our recent efforts focused on the design of polymeric micelle nanocarriers tailored for the selective transport and release of hLDHA inhibitors into liver tissues. In this study, we synthesized and assessed the internalization and disaggregation dynamics of chitosan-based polymeric micelles in both hepatic and nonhepatic cell models using live-cell imaging. Our findings indicate that lactonolactone residues confer internalization capacity to the micelles upon exposure to cells. Moreover, we demonstrated the intracellular disaggregation capacity of these nanocarriers facilitated by the cystamine redox-sensitive linker attached to the polymer. Importantly, no cytotoxic effects were observed throughout the experimental time frame. Finally, our results underscore the higher selectivity of these nanocarriers for hepatic HepG2 cells compared to other nonhepatic cell models.

Efficacy and safety of lumasiran for infants and young children with primary hyperoxaluria type 1: 30-month analysis of the phase 3 ILLUMINATE-B trial

BackgroundPrimary hyperoxaluria type 1 (PH1) is a genetic disorder resulting in overproduction of hepatic oxalate, potentially leading to recurrent kidney stones, nephrocalcinosis, chronic kidney disease, and kidney failure. Lumasiran, the first RNA interference therapeutic approved for infants and young children, is a liver-directed treatment that reduces hepatic oxalate production. Lumasiran demonstrated sustained efficacy with an acceptable safety profile over 12 months in infants and young children (age &amp;lt;6 years) with PH1 in ILLUMINATE-B (clinicaltrials.gov: NCT03905694), an ongoing, Phase 3, multinational, open-label, single-arm study.MethodsHere, we report interim efficacy and safety findings from ILLUMINATE-B following 30 months of lumasiran treatment. Eligible patients had an estimated glomerular filtration rate (eGFR) &amp;gt;45 ml/min/1.73 m2 if ≥12 months old or normal serum creatinine if &amp;lt;12 months old, and a urinary oxalate to creatinine ratio (UOx:Cr) greater than the upper limit of normal. All 18 patients enrolled in ILLUMINATE-B completed the 6-month primary analysis period, entered an extension period of up to 54 months, and continue to participate in the study.ResultsAt Month 30, mean percent change from baseline in spot UOx:Cr was −76%, and mean percent change in plasma oxalate was −42%. eGFR remained stable through Month 30. In 14 patients (86%) with nephrocalcinosis at baseline, nephrocalcinosis grade improved at Month 24 in 12; no patient worsened. In the 4 patients without baseline nephrocalcinosis, nephrocalcinosis was absent at Month 24. Kidney stone event rates were ≤0.25 per person-year through Month 30. Mild, transient injection site reactions were the most common lumasiran-related adverse events (17% of patients).ConclusionIn infants and young children with PH1, long-term lumasiran treatment resulted in sustained reductions in urinary and plasma oxalate that were sustained for 30 months, with an acceptable safety profile. Kidney function remained stable, low kidney stone event rates were observed through Month 30, and nephrocalcinosis grade improvements were observed through Month 24. Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT03905694.

A case report on primary hyperoxaluria type 1 in an infant

An alanine-glyoxylate aminotransferase (AGT) deficiency causes elevated oxalate levels in primary hyperoxaluria type 1 (PH1), a rare genetic disorder that can cause renal complications. We report the case of a 3-month-old male infant with respiratory distress, decreased urine output, and metabolic acidosis who was born to consanguineous parents. Bilateral nephrocalcinosis and severe metabolic disturbances were found during further examinations. Prompt identification and genetic validation for therapeutic interventions guided by PH1, such as peritoneal dialysis. The severity of PH1 was highlighted by difficulties maintaining renal function even after an initial improvement. To lessen the severe effects of PH1, this case highlights the significance of early diagnosis, genetic evaluation, and multidisciplinary management.