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Retinal Cases & Brief Reports Dec 2023To report the case of severe bilateral retinal vascular occlusion in a patient with hyperoxalosis and chronic renal failure.
PURPOSE
To report the case of severe bilateral retinal vascular occlusion in a patient with hyperoxalosis and chronic renal failure.
METHODS
Observational case report. Medical and imaging records were retrospectively reviewed. The patient was imaged with ultra-widefield (UWF) fundus photography and fluorescein angiography (UWF-FA), cross sectional and en face spectral-domain optical coherence tomography (SD-OCT), and OCT angiography.
RESULTS
A 32-year-old diabetic patient receiving peritoneal dialysis was referred because of severe vision loss. UWF color fundus photography showed diffuse sclerotic retinal vessels and diffuse intraretinal crystals in both eyes. UWF-FA illustrated near-complete retinal vascular occlusion and capillary wipe out in both eyes. SD-OCT demonstrated diffuse inner and middle retina thinning in both eyes and multiple intraretinal hyperreflective foci consistent with crystalline deposits in all retina layers of both eyes. OCT angiography revealed severe capillary and large vessel non-perfusion in the superficial and deep retinal capillary plexus of each eye. The serum oxalate levels were increased at 28 µmol/L (reference range < 2 µmol/L) and genetic testing was positive for a heterozygous mutation of the AGXT (Alanine-Glyoxylate Amino Transferase) gene that causes type 1 autosomal recessive primary hyperoxaluria.
CONCLUSION
A diagnosis of hyperoxalosis causing severe retinal vascular occlusion was rendered. Hyperoxalosis was the result of multiple factors including heterozygous AGXT mutation, chronic renal failure insufficiently treated with peritoneal dialysis, and a diet high in oxalate. This case highlights the importance of ruling out retinal oxalosis in patients on peritoneal dialysis in order to initiate prompt hemodialysis and prevent severe retinal vascular occlusion.
PubMed: 38055904
DOI: 10.1097/ICB.0000000000001519 -
Pediatric Nephrology (Berlin, Germany) Jun 2024A 6-month-old girl, previously diagnosed with cystic fibrosis (CF), was admitted to hospital for nephrolithiasis. Her parents were first-degree cousins. The patient...
A 6-month-old girl, previously diagnosed with cystic fibrosis (CF), was admitted to hospital for nephrolithiasis. Her parents were first-degree cousins. The patient underwent endoscopic stone management. Despite no family history of stones and medical treatment with potassium citrate, the patient developed recurrent renal stones and atypical urinary tract infections during follow-up. Basic investigations were all normal. Due to consanguinity and early presentation of nephrolithiasis, metabolic causes such as cystinuria and hyperoxaluria were considered. Cystinuria was excluded due to normal cystine levels. High urinary oxalate excretion was found as expected due to absorptive (secondary) hyperoxaluria in CF patients. An early stone burden in the patient with a history of medical treatment and consanguinity led us to perform a genetic testing. Genetic testing revealed a missense homozygous variant in exon 1 of the AGXT gene. The patient was diagnosed with primary hyperoxaluria type 1. Two rare life-threatening genetic diseases were found together in the same child.
PubMed: 38916781
DOI: 10.1007/s00467-024-06433-2 -
Biomolecules Apr 2024Primary hyperoxalurias (PHs) are inherited metabolic disorders marked by enzymatic cascade disruption, leading to excessive oxalate production that is subsequently... (Review)
Review
Primary hyperoxalurias (PHs) are inherited metabolic disorders marked by enzymatic cascade disruption, leading to excessive oxalate production that is subsequently excreted in the urine. Calcium oxalate deposition in the renal tubules and interstitium triggers renal injury, precipitating systemic oxalate build-up and subsequent secondary organ impairment. Recent explorations of novel therapeutic strategies have challenged and necessitated the reassessment of established management frameworks. The execution of diverse clinical trials across various medication classes has provided new insights and knowledge. With the evolution of PH treatments reaching a new milestone, prompt and accurate diagnosis is increasingly critical. Developing early, effective management and treatment plans is essential to improve the long-term quality of life for PH patients.
Topics: Humans; Hyperoxaluria, Primary; Calcium Oxalate; Oxalates; Quality of Life
PubMed: 38785918
DOI: 10.3390/biom14050511 -
Kidney International Reports Jan 2024The RNA interference (RNAi) medication lumasiran reduces hepatic oxalate production in primary hyperoxaluria type 1 (PH1). Data outside clinical trials are scarce.
INTRODUCTION
The RNA interference (RNAi) medication lumasiran reduces hepatic oxalate production in primary hyperoxaluria type 1 (PH1). Data outside clinical trials are scarce.
METHODS
We report on retrospectively and observationally obtained data in 33 patients with PH1 (20 with preserved kidney function, 13 on dialysis) treated with lumasiran for a median of 18 months.
RESULTS
Among those with preserved kidney function, mean urine oxalate (Uox) decreased from 1.88 (baseline) to 0.73 mmol/1.73 m per 24h after 3 months, to 0.72 at 12 months, and to 0.65 at 18 months, but differed according to vitamin B6 (VB6) medication. The highest response was at month 4 (0.55, -70.8%). Plasma oxalate (Pox) remained stable over time. Glomerular filtration rate increased significantly by 10.5% at month 18. Nephrolithiasis continued active in 6 patients, nephrocalcinosis ameliorated or progressed in 1 patient each. At last follow-up, Uox remained above 1.5 upper limit of normal (>0.75 mmol/1.73 m per 24h) in 6 patients. Urinary glycolate (Uglyc) and plasma glycolate (Pglyc) significantly increased in all, urine citrate decreased, and alkali medication needed adaptation. Among those on dialysis, mean Pox and Pglyc significantly decreased and increased, respectively after monthly dosing (Pox: 78-37.2, Pglyc: 216.4-337.4 μmol/l). At quarterly dosing, neither Pox nor Pglyc were significantly different from baseline levels. An acid state was buffered by an increased dialysis regimen. Systemic oxalosis remained unchanged.
CONCLUSION
Lumasiran treatment is safe and efficient. Dosage (interval) adjustment necessities need clarification. In dialysis, lack of Pox reduction may relate to dissolving systemic oxalate deposits. Pglyc increment may be a considerable acid load requiring careful consideration, which definitively needs further investigation.
PubMed: 38312792
DOI: 10.1016/j.ekir.2023.10.004 -
Clinical Pharmacology in Drug... Dec 2023Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its...
Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure-response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30 mL/min/1.73 m (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10 participants with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m ; Group 3) received a single dose of subcutaneous nedosiran sodium 170 mg. Group 1a received nedosiran 8 hours before beginning hemodialysis, Group 1b received nedosiran 2 hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic-pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24-hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.
Topics: Humans; Renal Insufficiency, Chronic; Renal Dialysis; Glomerular Filtration Rate
PubMed: 37605486
DOI: 10.1002/cpdd.1320 -
Kidney International Reports May 2024Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is an RNA interference (RNAi) therapeutic that the US Food and Drug...
INTRODUCTION
Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is an RNA interference (RNAi) therapeutic that the US Food and Drug Administration has approved for treatment of PH1. PHYOX3 is a trial evaluating monthly nedosiran in patients with PH.
METHODS
In this PHYOX3 interim analysis, participants with PH1 who continued from a single-dose nedosiran trial (PHYOX1), with no previous kidney or liver transplantation, dialysis, or evidence of systemic oxalosis were eligible. The safety and efficacy of once-monthly nedosiran was assessed over 30 months.
RESULTS
Thirteen participants completed PHYOX1 and continued into PHYOX3. At baseline, the mean (SD) and median (range) age was 24.2 (6.6) years and 23.0 (14-39) years, respectively; 53.8% were female and 61.5% were White. Mean estimated glomerular filtration rate (eGFR) remained stable (62-84.2 mL/min per 1.73 m) to month 30. Mean 24-hour urinary oxalate (Uox) excretion showed a sustained reduction from baseline of ≥60% at every visit (months 2-30). From month 2, at least 10 of 13 (76.9%) participants achieved normal (<0.46 mmol/24h; upper limit of assay-normal [ULN]) or near-normal (≥0.46 to <0.60 mmol/24h; ≥ULN to <1.3 × ULN) 24-hour Uox excretion. All participants experienced ≥1 adverse event (AE), mostly mild or moderate in severity (primarily, injection site events). Three serious, not treatment-related AEs were reported; there were no deaths or study discontinuations due to AEs.
CONCLUSION
Nedosiran was well-tolerated in patients with PH1, and treatment resulted in a sustained, substantial reduction in Uox excretion for at least 30 months in this long-term study. No safety signals have been identified to date. The PHYOX3 study is ongoing.
PubMed: 38707801
DOI: 10.1016/j.ekir.2024.02.1439 -
Current Rheumatology Reviews 2024Primary hyperoxaluria consists of a group of inherited disorders with enzymatic defects in the glyoxylate pathway, leading to decreased oxalate metabolism. The resulting... (Review)
Review
BACKGROUND
Primary hyperoxaluria consists of a group of inherited disorders with enzymatic defects in the glyoxylate pathway, leading to decreased oxalate metabolism. The resulting oxalic deposition is specifically responsible for kidney disease and joint disease. Neonatal oxalosis is the most severe form of primary hyperoxia type 1, with the onset of end-stage renal disease in childhood.
CASE PRESENTATION
A 55-year-old hemodialysis man was referred to Nephrology because of inflammatory polyarthralgia and periarticular swelling evolving for six months. He had been on hemodialysis for six years for end-stage chronic renal failure, diagnosed at the same time as primary hyperoxaluria. Radiological investigation showed a rugby jersey appearance on the lumbar spine, budding calcium tone opacities next to large joints and clavicles, vascular calcifications and tumoral calcinosis. The synovial fluid contained a few cells with polymorphic intracellular crystals. We ruled out hyperparathyroidism, hypoparathyroidism, and related phosphocalcic disorders, and we retained arthropathy and tumoral calcinosis secondary to primary hyperoxaliuria. The patient also had congestive heart failure. Despite intensification of hemodialysis, he did not improve and died at the age of 56 in the context of cachexia.
CONCLUSION
This rare case documents the possible occurrence of late clinical presentation and long survival in primary oxalosis with extra renal complications.
Topics: Humans; Male; Middle Aged; Hyperoxaluria, Primary; Calcinosis; Renal Dialysis; Kidney Failure, Chronic; Fatal Outcome; Crystal Arthropathies; Joint Diseases
PubMed: 38243963
DOI: 10.2174/0115733971271874231118154332 -
Jornal Brasileiro de Nefrologia 2024
Topics: Humans; Hyperoxaluria, Primary; X-Rays; Radiography, Abdominal; Kidney Calculi
PubMed: 38358912
DOI: 10.1590/2175-8239-JBN-2023-0032en -
Therapeutic Apheresis and Dialysis :... Aug 2023
Topics: Pregnancy; Female; Humans; Hyperoxaluria, Primary; Renal Dialysis
PubMed: 37073104
DOI: 10.1111/1744-9987.13995 -
IScience Apr 2024Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused...
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused by mutations in the gene. Combined liver and kidney transplantation is currently the only permanent curative treatment. We combined locus-specific gene correction and hepatic direct cell reprogramming to generate autologous healthy induced hepatocytes (iHeps) from PH1 patient-derived fibroblasts. First, site-specific corrected cells were obtained by homology directed repair (HDR) assisted by CRISPR-Cas9, following two different strategies: accurate point mutation (c.731T>C) correction or knockin of an enhanced version of cDNA. Then, iHeps were generated, by overexpression of hepatic transcription factors. Generated -corrected iHeps showed hepatic gene expression profile and exhibited reversion of oxalate accumulation compared to non-edited PH1-derived iHeps. This strategy set up a potential alternative cellular source for liver cell replacement therapy and a personalized PH1 disease model.
PubMed: 38577102
DOI: 10.1016/j.isci.2024.109530