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Nephrology, Dialysis, Transplantation :... Jun 2023
Topics: Humans; Oxalates; Renal Dialysis; Hyperoxaluria, Primary; Glycolates; Hyperoxaluria
PubMed: 36898675
DOI: 10.1093/ndt/gfad049 -
The Journal of Urology Jun 2023Hallmarks of primary hyperoxaluria type 3 are nephrolithiasis and hyperoxaluria. However, little is known about factors influencing stone formation in this disease. We...
PURPOSE
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.
MATERIALS AND METHODS
We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry.
RESULTS
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]; < .001). By the fourth decade, estimated glomerular filtration rate was lower in primary hyperoxaluria type 3 patients than the general population.
CONCLUSIONS
Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.
Topics: Humans; Child, Preschool; Calcium Oxalate; Hyperoxaluria, Primary; Retrospective Studies; Kidney Calculi; Hyperoxaluria
PubMed: 36888927
DOI: 10.1097/JU.0000000000003400 -
Nucleic Acids Research Apr 2023Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides... (Review)
Review
Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. Among the diseases targeted by this new class of drugs are homozygous familial hypercholesterolemia, spinal muscular atrophy, Duchenne muscular dystrophy, hereditary transthyretin-mediated amyloidosis, familial chylomicronemia syndrome, acute hepatic porphyria, and primary hyperoxaluria. Chemical modification of DNA and RNA was central to making drugs out of oligonucleotides. Oligonucleotide therapeutics brought to market thus far contain just a handful of first- and second-generation modifications, among them 2'-fluoro-RNA, 2'-O-methyl RNA and the phosphorothioates that were introduced over 50 years ago. Two other privileged chemistries are 2'-O-(2-methoxyethyl)-RNA (MOE) and the phosphorodiamidate morpholinos (PMO). Given their importance in imparting oligonucleotides with high target affinity, metabolic stability and favorable pharmacokinetic and -dynamic properties, this article provides a review of these chemistries and their use in nucleic acid therapeutics. Breakthroughs in lipid formulation and GalNAc conjugation of modified oligonucleotides have paved the way to efficient delivery and robust, long-lasting silencing of genes. This review provides an account of the state-of-the-art of targeted oligo delivery to hepatocytes.
Topics: Humans; Morpholinos; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; RNA; RNA Interference
PubMed: 36881759
DOI: 10.1093/nar/gkad067 -
World Journal of Clinical Cases Feb 2023Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease stemming from a deficiency in liver-specific alanine-glyoxylate aminotransferase, resulting in...
BACKGROUND
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease stemming from a deficiency in liver-specific alanine-glyoxylate aminotransferase, resulting in increased endogenous oxalate deposition and end-stage renal disease. Organ transplantation is the only effective treatment. However, its approach and timing remain controversial.
CASE SUMMARY
We retrospectively analyzed 5 patients diagnosed with PH1 from the Liver Transplant Center of the Beijing Friendship Hospital from March 2017 to December 2020. Our cohort included 4 males and 1 female. The median age at onset was 4.0 years (range: 1.0-5.0), age at diagnosis was 12.2 years (range: 6.7-23.5), age at liver transplantation (LT) was 12.2 years (range: 7.0-25.1), and the follow-up time was 26.3 mo (range: 12.8-40.1). All patients had delayed diagnosis, and 3 patients had progressed to end-stage renal disease by the time they were diagnosed. Two patients received preemptive LT; their estimated glomerular filtration rate was maintained at > 120 mL/min/1.73 m, indicating a better prognosis. Three patients received sequential liver and kidney transplantation. After transplantation, serum and urinary oxalate decreased, and liver function recovered. At the last follow-up, the estimated glomerular filtration rates of the latter 3 patients were 179, 52 and 21 mL/min/1.73 m.
CONCLUSION
Different transplantation strategies should be adopted for patients based on their renal function stage. Preemptive-LT offers a good therapeutic approach for PH1.
PubMed: 36874433
DOI: 10.12998/wjcc.v11.i5.1068 -
Glycolate oxidase inhibition by lumasiran varies between patients with primary hyperoxaluria type 1.Kidney International May 2023
Topics: Humans; Hyperoxaluria, Primary; Alcohol Oxidoreductases; Hyperoxaluria; Oxalates
PubMed: 36871948
DOI: 10.1016/j.kint.2023.01.029 -
Journal of Medical Economics 2023Quantitative 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...
AIMS
Quantitative 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 METHODS
Health 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.
RESULTS
A 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.
LIMITATIONS
Vignettes may not fully capture the burden of living with PH1.
CONCLUSIONS
This 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.
Topics: Humans; Quality of Life; Hyperoxaluria, Primary; Renal Insufficiency, Chronic; Liver Transplantation; Health Status; Surveys and Questionnaires
PubMed: 36852648
DOI: 10.1080/13696998.2023.2176678 -
International Journal of Surgery... Feb 2023
Topics: Humans; Hyperoxaluria, Primary; RNA, Small Interfering; Hyperoxaluria
PubMed: 36799810
DOI: 10.1097/JS9.0000000000000143 -
Nutrients Feb 2023Renal lithiasis is less frequent in children than in adults; in pediatrics, lithiasis may be caused by genetic abnormalities, infections, and complex uropathies, but the... (Review)
Review
Renal lithiasis is less frequent in children than in adults; in pediatrics, lithiasis may be caused by genetic abnormalities, infections, and complex uropathies, but the association of urological and metabolic abnormalities is not uncommon. The aim of this study is to provide a synthesis of nephrolithiasis in children and to emphasize the role of hydration in its treatment. As an etiology is reported in 50% of cases, with a genetic origin in 10 to 20%, it is proposed to systematically perform a complete metabolic assessment after the first stone in a child. Recent data in the field reported increased incidence of pediatric urolithiasis notably for calcium oxalate stones. These changes in the epidemiology of stone components may be attributable to metabolic and environmental factors, where hydration seems to play a crucial role. In case of pediatric urolithiasis, whatever its cause, it is of utmost importance to increase water intake around 2 to 3 L/m per day on average. The objective is to obtain a urine density less than 1010 on a dipstick or below 300 mOsm/L, especially with the first morning urine. Some genetic diseases may even require a more active 24 h over-hydration, e.g., primary hyperoxaluria and cystinuria; in such cases naso-gastric tubes or G-tubes may be proposed. Tap water is adapted for children with urolithiasis, with limited ecological impact and low economical cost. For children with low calcium intake, the use of calcium-rich mineral waters may be discussed in some peculiar cases, even in case of urolithiasis. In contrast, sugar-sweetened beverages are not recommended. In conclusion, even if parents and patients sometimes have the feeling that physicians do not propose "fancy" therapeutic drugs, hydration and nutrition remain cornerstones of the management of pediatric urolithiasis.
Topics: Adult; Child; Humans; Calcium; Lithiasis; Kidney Calculi; Urolithiasis; Cystinuria
PubMed: 36771434
DOI: 10.3390/nu15030728 -
Journal of Clinical and Translational... 2023Time-dependent Cox proportional hazards regression is a popular statistical method used in kidney disease research to evaluate associations between biomarkers collected...
BACKGROUND
Time-dependent Cox proportional hazards regression is a popular statistical method used in kidney disease research to evaluate associations between biomarkers collected serially over time with progression to kidney failure. Typically, biomarkers of interest are considered time-dependent covariates being updated at each new measurement using last observation carried forward (LOCF). Recently, joint modeling has emerged as a flexible alternative for multivariate longitudinal and time-to-event data. This study describes and demonstrates multivariate joint modeling using as an example the association of serial biomarkers (plasma oxalate [POX] and urinary oxalate [UOX]) and kidney function among patients with primary hyperoxaluria in the Rare Kidney Stone Consortium Registry.
METHODS
Time-to-kidney failure was regressed on serially measured biomarkers in two ways: time-dependent LOCF Cox proportional hazards regression and multivariate joint models.
RESULTS
In time-dependent LOCF Cox regression, higher POX was associated with increased risk of kidney failure (HR = 2.20 per doubling, 95% CI = [1.38-3.51], p < 0.001) whereas UOX was not (HR = 1.08 per doubling, [0.66-1.77], p = 0.77). In multivariate joint models, estimates suggest higher UOX may be associated with lower risk of kidney failure (HR = 0.42 per doubling [0.15-1.04], p = 0.066), though not statistically significant, since impaired urinary excretion of oxalate may reflect worsening kidney function.
CONCLUSIONS
Multivariate joint modeling is more flexible than LOCF and may better reflect biological plausibility since biomarkers are not steady-state values between measurements. While LOCF is preferred to naïve methods not accounting for changes in biomarkers over time, results may not accurately reflect flexible relationships that can be captured with multivariate joint modeling.
PubMed: 36755528
DOI: 10.1017/cts.2022.465