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Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias., (© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Introduction: Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G>A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies., Methods: In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses., Results: The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G>A and c.454T>A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T>C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes ( P  = 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P  < 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure ( P  = 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals., Conclusion: In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

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., (© 2022. The Author(s).)

The clinical presentation of primary hyperoxaluria in children ranges from mildly symptomatic nephrocalcinosis to very early onset end-stage kidney failure with systemic oxalosis, a devastating complication. We review the various manifestations of pediatric hyperoxaluria, treatment options for children with preserved kidney function and appropriate dialysis regimens. Liver or combined liver/kidney transplantation is currently the only definitive treatment for primary hyperoxaluria type 1, but novel RNA interference treatments offer hope for the future. Finally, we address the medical and ethical dilemmas facing pediatricians treating children with hyperoxaluria., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: Infantile oxalosis is the most severe form of primary hyperoxaluria type 1 (PH1), with onset of end-stage kidney disease (ESKD) during infancy . We aimed to analyze the outcome of these patients as our current understanding is limited owing to a paucity of reports., Methods: A retrospective registry study was conducted using data from the OxalEurope registry. All PH1 patients with ESKD onset at age <1 year were analyzed., Results: We identified 95 patients born between 1980 and 2018 with infantile oxalosis. Median (interquartile range [IQR]) age at ESKD was 0.4 (0.3-0.5) year. There were 4 patients diagnosed by family screening who developed ESKD despite early diagnosis. There were 11 patients who had biallelic missense mutations associated with vitamin B6 responsiveness. Of 89 patients, 27 (30%) died at a median age of 1.4 (0.6-2.0) years (5-year patient survival of 69%). Systemic oxalosis was described in 54 of 56 screened patients (96%). First transplantation was performed at a median age of 1.7 (1.3-2.9) years. In 42 cases, this procedure was a combined liver-kidney transplantation (LKTx), and in 23 cases, liver transplantations (LTx) was part of a sequential procedure. Survival rates of both strategies were similar. Patient survival was significantly higher in patients born after 2000. Intrafamilial phenotypic variability was present in 14 families of patients with infantile oxalosis., Conclusion: Nearly all screened patients with infantile oxalosis developed systemic disease. Mortality is still high but has significantly improved over time and might further improve under new therapies. The intrafamilial phenotypic variability warrants further investigation., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels., Methods: We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran)., Results: In the lumasiran/lumasiran group ( n  = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group ( n  = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs)., Conclusion: Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism, characterized by increased endogenous oxalate production. The metabolic pathways underlying oxalate synthesis have not been fully elucidated, and upcoming therapies require more reliable outcome parameters than the currently used plasma oxalate levels and urinary oxalate excretion rates. We therefore developed a stable isotope infusion protocol to assess endogenous oxalate synthesis rate and the contribution of glycolate to both oxalate and glycine synthesis in vivo ., Methods: Eight healthy volunteers and eight patients with PH1 (stratified by pyridoxine responsiveness) underwent a combined primed continuous infusion of intravenous [1- 13 C]glycolate, [U- 13 C 2 ]oxalate, and, in a subgroup, [D 5 ]glycine. Isotopic enrichment of 13 C-labeled oxalate and glycolate were measured using a new gas chromatography-tandem mass spectrometry (GC-MS/MS) method. Stable isotope dilution and incorporation calculations quantified rates of appearance and synthetic rates, respectively., Results: Total daily oxalate rates of appearance (mean [SD]) were 2.71 (0.54), 1.46 (0.23), and 0.79 (0.15) mmol/d in patients who were pyridoxine unresponsive, patients who were pyridoxine responsive, and controls, respectively ( P =0.002). Mean (SD) contribution of glycolate to oxalate production was 47.3% (12.8) in patients and 1.3% (0.7) in controls. Using the incorporation of [1- 13 C]glycolate tracer in glycine revealed significant conversion of glycolate into glycine in pyridoxine responsive, but not in patients with PH1 who were pyridoxine unresponsive., Conclusions: This stable isotope infusion protocol could evaluate efficacy of new therapies, investigate pyridoxine responsiveness, and serve as a tool to further explore glyoxylate metabolism in humans., (Copyright © 2021 by the American Society of Nephrology.)

Introduction: In primary hyperoxaluria type 1 (PH1), oxalate overproduction frequently causes kidney stones, nephrocalcinosis, and kidney failure. As PH1 is caused by a congenital liver enzyme defect, combined liver-kidney transplantation (CLKT) has been recommended in patients with kidney failure. Nevertheless, systematic analyses on long-term transplantation outcomes are scarce. The merits of a sequential over combined procedure regarding kidney graft survival remain unclear as is the place of isolated kidney transplantation (KT) for patients with vitamin B6-responsive genotypes., Methods: We used the OxalEurope registry for retrospective analyses of patients with PH1 who underwent transplantation. Analyses of crude Kaplan-Meier survival curves and adjusted relative hazards from the Cox proportional hazards model were performed., Results: A total of 267 patients with PH1 underwent transplantation between 1978 and 2019. Data of 244 patients (159 CLKTs, 48 isolated KTs, 37 sequential liver-KTs [SLKTs]) were eligible for comparative analyses. Comparing CLKTs with isolated KTs, adjusted mortality was similar in patients with B6-unresponsive genotypes but lower after isolated KT in patients with B6-responsive genotypes (adjusted hazard ratio 0.07, 95% CI: 0.01-0.75, P  = 0.028). CLKT yielded higher adjusted event-free survival and death-censored kidney graft survival in patients with B6-unresponsive genotypes ( P  = 0.025, P  < 0.001) but not in patients with B6-responsive genotypes ( P  = 0.145, P  = 0.421). Outcomes for 159 combined procedures versus 37 sequential procedures were comparable. There were 12 patients who underwent pre-emptive liver transplantation (PLT) with poor outcomes., Conclusion: The CLKT or SLKT remains the preferred transplantation modality in patients with PH1 with B6-unresponsive genotypes, but isolated KT could be an alternative approach in patients with B6-responsive genotypes., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Outcome data in primary hyperoxaluria type 3 (PH3), described as a less severe form of the PH's with a low risk of chronic kidney disease, are scarce. To investigate this, we retrospectively analyzed the largest PH3 cohort reported so far. Of 95 patients, 74 were followed over a median of six years. Median age of first symptoms and diagnosis were 1.9 and 6.3 years, respectively. Urolithiasis was the major clinical feature observed in 70% of pediatric and 50% of adult patients. At most recent follow-up available for 56 of the 95 patients, 21.4% were in chronic kidney disease stages 2 or more. For better characterization, samples from 49 patients were analyzed in a single laboratory and compared to data from patients with PH1 and PH2 from the same center. Urinary oxalate excretion was not significantly different from PH1 and PH2 (median: 1.37, 1.40 and 1.16 mmol/1.73m 2 /24hours for PH1 not responsive to vitamin B6, PH2, and PH3, respectively) but was significantly higher than in vitamin B6 responsive patients with PH1. Urinary oxalate excretion did not correlate to stone production rate nor to estimated glomerular filtration rate. Normocitraturia was present even without alkalinisation treatment; hypercalciuria was found rarely. Median plasma oxalate was significantly different only to the vitamin B6-unresponsive PH1 group. Thus, PH3 is more comparable to PH1 and PH2 than so far inferred from smaller studies. It is the most favorable PH type, but not a benign entity as it constitutes an early onset, recurrent stone disease, and kidney function can be impaired., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Primary hyperoxaluria type 1 (PH1) is characterized by hepatic overproduction of oxalate and often results in kidney failure. Liver-kidney transplantation is recommended, either combined (CLKT) or sequentially performed (SLKT). The merits of SLKT and the place of an isolated kidney transplant (KT) in selected patients are unsettled. We systematically reviewed the literature focusing on patient and graft survival rates in relation to the chosen transplant strategy., Methods: We searched MEDLINE and Embase using a broad search string, consisting of the terms 'transplantation' and 'hyperoxaluria'. Studies reporting on at least four transplanted patients were selected for quality assessment and data extraction., Results: We found 51 observational studies from 1975 to 2020, covering 756 CLKT, 405 KT and 89 SLKT, and 51 pre-emptive liver transplantations (PLT). Meta-analysis was impossible due to reported survival probabilities with varying follow-up. Two individual high-quality studies showed an evident kidney graft survival advantage for CLKT versus KT (87% vs. 14% at 15 years, p<0.05) with adjusted HR for graft failure of 0.14 (95% confidence interval: 0.05-0.41), while patient survival was similar. Three other high-quality studies reported 5-year kidney graft survival rates of 48-89% for CLKT and 14-45% for KT. PLT and SLKT yielded 1-year patient and graft survival rates up to 100% in small cohorts., Conclusions: Our study suggests that CLKT leads to superior kidney graft survival compared to KT. However, evidence for merits of SLKT or for KT in pyridoxine-responsive patients was scarce, which warrants further studies, ideally using data from a large international registry.

Primary hyperoxalurias (PH) are inborn errors of glyoxylate metabolism characterized by an increase in endogenous oxalate production. Oxalate overproduction may cause calcium-oxalate crystal formation leading to kidney stones, nephrocalcinosis, and ultimately kidney failure. Twenty-four hour urine oxalate excretion is an inaccurate measure for endogenous oxalate production in PH patients and not applicable in those with kidney failure. Treatment efficacy cannot be assessed with this measure during clinical trials. We describe the development and validation of a gas chromatography-tandem mass spectrometry method to analyze the samples obtained following a stable isotope infusion protocol of 13 C 2 -oxalate and 1- 13 C-glycolate in both healthy individuals and PH patients. Isotopic enrichments of plasma oxalate, glycolate, and glyoxylate were measured on a gas chromatography-triple quadrupole mass spectrometry system using ethylhydroxylamine and N - tert -butyldimethylsilyl- N -methyltrifluoroacetamide (MTBSTFA) for analyte derivatization. Method precision was good for oxalate and glycolate (coefficients of variation [CV] were <6.3% and <4.2% for inter- and intraday precision, respectively) and acceptable for glyoxylate (CV <18.3% and <6.7% for inter- and intraday precision, respectively). The enrichment curves were linear over the specified range. Sensitivity was sufficient to accurately analyze enrichments. This new method allowed calculation of kinetic features of these metabolites, thus enabling a detailed analysis of the various pathways involved in glyoxylate metabolism. The method will further enhance the investigation of the metabolic PH derangements, provides a tool to accurately assess the therapeutic efficacy of new promising therapeutic interventions for PH, and could serve as a clinical tool to improve personalized therapeutic strategies.

Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, primary hyperoxaluria type 2 was considered to have a more favorable prognosis than primary hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with primary hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, primary hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up., (Copyright © 2019 International Society of Nephrology. All rights reserved.)

Purpose: To investigate ophthalmic features in a large group of patients with primary hyperoxaluria type 1 (PH1) and to determine the relation between ocular involvement and systemic disease severity., Design: Retrospective, cross-sectional, multicenter study of the OxalEurope Registry Network., Methods: Sixty-eight patients with PH1 were included. Infantile PH1 was diagnosed in 12 patients, and non-infantile PH1 was diagnosed in 56 patients (17 with end-stage renal disease). Ophthalmic examination included best corrected visual acuity (BCVA) testing and multimodal retinal imaging, including fundus photography and optical coherence tomography (OCT). In selected cases, fundus autofluorescence imaging was performed., Results: All eyes (n = 24) of infantile PH1 patients revealed severe retinal alterations and oxalate deposits, including macular crystals and hyperpigmentations (n = 9, 38%), and subretinal fibrosis (n = 15, 63%) with (n = 7, 47%) or without (n = 8; 53%) associated chronic retinal edema. In 9 eyes (38%, all with subretinal fibrosis), BCVA was significantly reduced (<20/50 Snellen equivalent). In contrast, all eyes (n = 112) of patients with non-infantile PH1 had a BCVA in the normal range (median, 20/20). Only 6 patients with non-infantile disease (11%, all with end-stage renal disease) showed mild, likely PH1-related retinal features. These deposits appeared as focal hyperreflective subretinal lesions on OCT imaging and were hyperautofluorescent on autofluorescence images., Conclusions: Severe ocular alterations occur in infantile cases, whereas mild or no ocular alterations are typical in non-infantile PH1 patients. The natural history of (sub)retinal oxalate deposits, the pathogenesis of subretinal fibrosis, and exact factors influencing the overall severity of ocular disease manifestation remain to be determined., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Primary hyperoxalurias (PH) are devastating, autosomal recessive diseases causing renal stones. Undifferentiated hyperoxaluria is seen in up to 43% of Pakistani paediatric stone patients. High rates of consanguinity in Pakistan suggest significant local prevalence. There is no detailed information regarding number of cases, clinical features, and genetics in Pakistan-origin (P-o) patients. We reviewed available information on P-o PH patients recorded in the literature as well as from two major PH registries (the Rare Kidney Stone Consortium PH Registry (RKSCPHR) and the OxalEurope PH Registry (OxER); and the Aga Khan University Hospital in Pakistan. After excluding overlaps, we noted 217 P-o PH subjects (42 in OxER and 4 in RKSCPHR). Presentations were protean. Details of mutations were available for 94 patients of 201 who had genetic analyses. Unique mutations were noted. Mutation [c.508G>A (p. Gly170Arg)] (present in up to 25% in the West) was reported in only one case. In one series, only 30% had mutations on exons 1,4,7 of AGXT. Of 42 P-o patients in OxER, 52.4% were PH1, 45.2% PH2, and 2.4% PH3. Of concern is that diagnosis was made after renal transplant rejection (four cases) and on bone-marrow aspiration (in five). Lack of consideration of PH as a diagnosis, late diagnosis, and loss of transplanted kidneys mandates that PH be searched for diligently. Mutation analysis will need to extend to all exons and include PH 1,2,3. There is a need to spread awareness and identify patients through a scoring or screening system that alerts physicians to consider a diagnosis of PH.

Objective: To explore the association between psychiatric disorders as a comorbidity and return-to-work (RTW) in individuals with acquired brain injury (ABI)., Methods: A systematic review was performed. The search strategy (2002-2012) contained terms related to ABI, psychiatric comorbidity and keywords adapted to the outcome measure RTW. Selection and review were performed by two authors independently. In the case of uncertainty, a third author was consulted to reach consensus on inclusion or exclusion. The methodological quality of included studies was determined and evidence was classified., Results: Seven studies were included. Strong evidence was found for a negative association between psychiatric disorders as a comorbidity (like depression, anxiety and post-traumatic stress disorder) and RTW of patients with ABI. Patients with a previous history of psychiatric disorders were at considerably higher risk for a new episode and lower RTW rates following ABI., Conclusion and Implications: Psychiatric disorders as a comorbidity after ABI are strong negatively associated with RTW. The heightened frequency of psychiatric disorders as a comorbidity after ABI and more important their amenability to treatment implicates that more attention should be paid to diagnosing and treating psychiatric disorders as a comorbidity in patients with ABI in order to further improve re-integration in work.