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World Journal of Nephrology Nov 2014Hyperoxaluria can cause not only nephrolithiasis and nephrocalcinosis, but also renal parenchymal disease histologically characterized by deposition of calcium oxalate... (Review)
Review
Hyperoxaluria can cause not only nephrolithiasis and nephrocalcinosis, but also renal parenchymal disease histologically characterized by deposition of calcium oxalate crystals throughout the renal parenchyma, profound tubular damage and interstitial inflammation and fibrosis. Hyperoxaluric nephropathy presents clinically as acute or chronic renal failure that may progress to end-stage renal disease (ESRD). This sequence of events, well recognized in the past in primary and enteric hyperoxalurias, has also been documented in a few cases of dietary hyperoxaluria. Estimates of oxalate intake in patients with chronic dietary hyperoxaluria who developed chronic kidney disease or ESRD were comparable to the reported average oxalate content of the diets of certain populations worldwide, thus raising the question whether dietary hyperoxaluria is a primary cause of ESRD in these regions. Studies addressing this question have the potential of improving population health and should be undertaken, alongside ongoing studies which are yielding fresh insights into the mechanisms of intestinal absorption and renal excretion of oxalate, and into the mechanisms of development of oxalate-induced renal parenchymal disease. Novel preventive and therapeutic strategies for treating all types of hyperoxaluria are expected to develop from these studies.
PubMed: 25374807
DOI: 10.5527/wjn.v3.i4.122 -
Clinical Journal of the American... Jul 2021In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics.
RESULTS
Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal.
CONCLUSIONS
Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
Topics: Adolescent; Adult; Child; Female; Glycolates; Humans; Hyperoxaluria, Primary; Male; Oxalates; RNA, Small Interfering; Renal Agents; Single-Blind Method; Young Adult
PubMed: 33985991
DOI: 10.2215/CJN.14730920 -
Drugs Feb 2024Lumasiran (Oxlumo), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is... (Review)
Review
Lumasiran (Oxlumo), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is approved in several countries for patients of any age and stage of kidney function with primary hyperoxaluria type 1 (PH1). Approval was based on results from the phase III ILLUMINATE trials. In the double-blind, placebo-controlled, ILLUMINATE-A trial, subcutaneous lumasiran was significantly more effective than placebo in reducing 24-h urinary oxalate excretion in patients aged ≥ 6 years with PH1; this effect was sustained for ≥ 36 months in ongoing longer-term analyses. In the single-arm ILLUMINATE-B trial, lumasiran reduced urinary oxalate:creatinine ratios and plasma oxalate levels in patients aged < 6 years with PH1. In the single-arm ILLUMINATE-C trial, lumasiran reduced plasma oxalate levels in patients with PH1 receiving dialysis as well as those not receiving dialysis. In secondary and exploratory analyses of these trials, nephrocalcinosis grade, kidney stone event rates and estimated glomerular filtration rates were either stable or improved with lumasiran. Lumasiran had an acceptable tolerability profile that remained consistent in longer-term analyses; the most common adverse events were mild and transient injection-site reactions. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1.
Topics: Humans; Hyperoxaluria, Primary; Oxalates; RNA, Small Interfering; Randomized Controlled Trials as Topic
PubMed: 38252335
DOI: 10.1007/s40265-023-01987-1 -
Clinical Kidney Journal May 2022Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism characterized by marked hepatic overproduction of oxalate due to deficiency of... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism characterized by marked hepatic overproduction of oxalate due to deficiency of hepatic peroxisomal alanine-glyoxylate aminotransferase caused by gene mutation. One major hallmark of PH1 in developed as well as developing countries (DC) is the diagnostic delay. Notably in DC, where the disease is most prevalent and probably underdiagnosed, there are many challenges in PH1 diagnosis and management, with economic constrains and ethical concerns. This has led to the existing gap in the management of PH1 between developed and DC, which is expected to further deepen with the advent of novel therapeutic agents unless appropriate actions are taken. Until recently, treatment possibilities were limited to supportive measures. Thanks to a better understanding of the molecular basis of the disease a number of new therapies are developed, or being developed, leading to profound changes in management strategies. In this review we discuss the current situation of PH1 in DC as well as the accessibility challenges and the advantages of using promising novel therapeutics to bridge the currently existing gap. We also provide an overview of an integrated approach to ensure equitable access of sustainable therapeutics to PH1 patients in DC. This is expected to reduce global PH1 healthcare disparities, improve its standard of care and reduce disability linked to extrarenal complications of PH1 by implementing personalized medicine.
PubMed: 35592622
DOI: 10.1093/ckj/sfab203 -
International Journal of Surgery... Dec 2016Although the primary hyperoxalurias (PH) are rare disorders, they are of considerable clinical importance in relation to calcium oxalate urolithiasis and as a cause of... (Review)
Review
Although the primary hyperoxalurias (PH) are rare disorders, they are of considerable clinical importance in relation to calcium oxalate urolithiasis and as a cause of renal failure worldwide. Three distinct disorders have been described at the molecular level. The investigation of any child or adult presenting with urinary tract stones or nephrocalcinosis, must exclude PH as an underlying cause. This paper provides a practical approach to the investigation and diagnosis of PH, indicating the importance of distinguishing between the PH types for the purposes of targeting appropriate therapy. Conservative management is explored and the various transplant options are discussed.
Topics: Adult; Child; Diagnosis, Differential; Disease Management; Female; Humans; Hyperoxaluria, Primary; Male; Nephrocalcinosis; Nephrolithiasis; Oxalates; Renal Insufficiency; Urinary Calculi
PubMed: 27815184
DOI: 10.1016/j.ijsu.2016.10.039 -
Current Opinion in Nephrology and... Jul 2016Oxalate is an end product of metabolism excreted via the kidney. Excess urinary oxalate, whether from primary or enteric hyperoxaluria, can lead to oxalate deposition in... (Review)
Review
PURPOSE OF REVIEW
Oxalate is an end product of metabolism excreted via the kidney. Excess urinary oxalate, whether from primary or enteric hyperoxaluria, can lead to oxalate deposition in the kidney. Oxalate crystals are associated with renal inflammation, fibrosis, and progressive renal failure. It has long been known that as the glomerular filtration rate becomes reduced in chronic kidney disease (CKD), there is striking elevation of plasma oxalate. Taken together, these findings raise the possibility that elevation of plasma oxalate in CKD may promote renal inflammation and more rapid progression of CKD independent of primary cause.
RECENT FINDINGS
The inflammasome has recently been identified to play a critical role in oxalate-induced renal inflammation. Oxalate crystals have been shown to activate the NOD-like receptor family, pyrin domain containing 3 inflammasome (also known as NALP3, NLRP3, or cryopyrin), resulting in release of IL-1β and macrophage infiltration. Deletion of inflammasome proteins in mice protects from oxalate-induced renal inflammation and progressive renal failure.
SUMMARY
The findings reviewed in this article expand our understanding of the relevance of elevated plasma oxalate levels leading to inflammasome activation. We propose that inhibiting oxalate-induced inflammasome activation, or lowering plasma oxalate, may prevent or mitigate progressive renal damage in CKD, and warrants clinical trials.
Topics: Animals; Disease Progression; Fibrosis; Humans; Inflammasomes; Inflammation; Interleukin-1beta; Kidney; Macrophages; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Oxalates; Renal Insufficiency, Chronic
PubMed: 27191349
DOI: 10.1097/MNH.0000000000000229 -
Frontiers in Pediatrics 2021Oxalate overproduction in Primary Hyperoxaluria type I (PH1) leads to progressive renal failure and systemic oxalate deposition. In severe infantile forms of PH1...
Oxalate overproduction in Primary Hyperoxaluria type I (PH1) leads to progressive renal failure and systemic oxalate deposition. In severe infantile forms of PH1 (IPH1), end-stage renal disease (ESRD) occurs in the first years of life. Usually, the management of these infantile forms is challenging and consists in an intensive dialysis regimen followed by a liver-kidney transplantation (combined or sequential). Medical records of all infants with IPH1 reaching ESRD within the first year of life, diagnosed and followed between 2005 and 2018 in two pediatric nephrology departments in Brussels and Paris, have been reviewed. Seven patients were included. They reached ESRD at a median age of 3.5 (2-7) months. Dialysis was started at a median age of 4 (2-10 months). Peritoneal dialysis (PD) was the initial treatment for 6 patients and hemodialysis (HD) for one patient. Liver transplantation (LT) was performed in all patients and kidney transplantation (KT) in six of them. A sequential strategy has been chosen in 5 patients, a combined in one. The kidney transplanted as part of the combined strategy was lost. Median age at LT and KT was 25 (10-41) months and 32.5 (26-75) months, respectively. No death occurred in the series. At the end of a median follow-up of 3 years, mean eGFR was 64 ± 29 ml/min/1.73 m. All patients presented retinal and bone lesions and five patients presented bones fractures. Despite encouraging survival figures, the morbidity in IPH1 patients remains extremely heavy and its management presents a huge challenge. Thanks to the newly developed RNA-interference drug, the future holds brighter prospects.
PubMed: 33959570
DOI: 10.3389/fped.2021.615183 -
Zoological Research Nov 2023Targeting key enzymes that generate oxalate precursors or substrates is an alternative strategy to eliminate primary hyperoxaluria type I (PH1), the most common and...
Targeting key enzymes that generate oxalate precursors or substrates is an alternative strategy to eliminate primary hyperoxaluria type I (PH1), the most common and life-threatening type of primary hyperoxaluria. The compact Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) from the and (Cpf1) protein simplifies multiplex gene editing and allows for all-in-one adeno-associated virus (AAV) delivery. We hypothesized that the multiplex capabilities of the Cpf1 system could help minimize oxalate formation in PH1 by simultaneously targeting the hepatic hydroxyacid oxidase 1 ( ) and lactate dehydrogenase A ( ) genes. Study cohorts included treated PH1 rats ( rats injected with AAV-AsCpf1 at 7 days of age), phosphate-buffered saline (PBS)-injected PH1 rats, untreated PH1 rats, and age-matched wild-type (WT) rats. The most efficient and specific CRISPR RNA (crRNA) pairs targeting the rat and genes were initially screened . experiments demonstrated efficient genome editing of the and genes, primarily resulting in small deletions. This resulted in decreased transcription and translational expression of and . Treatment significantly reduced urine oxalate levels, reduced kidney damage, and alleviated nephrocalcinosis in rats with PH1. No liver toxicity, ex-liver genome editing, or obvious off-target effects were detected. We demonstrated the AAV-AsCpf1 system can target multiple genes and rescue the pathogenic phenotype in PH1, serving as a proof-of-concept for the development of multiplex genome editing-based gene therapy.
Topics: Animals; Rats; Gene Editing; Hyperoxaluria, Primary; Liver; Oxalates
PubMed: 37759334
DOI: 10.24272/j.issn.2095-8137.2022.495 -
Frontiers in Genetics 2023Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to...
Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to allelic and clinical heterogeneity. This study aimed to analyze the genotype of 21 Chinese patients with primary hyperoxaluria (PH) and explore their correlations between genotype and phenotype. Combined with clinical phenotypic and genetic analysis, we identified 21 PH patients from highly suspected Chinese patients. The clinical, biochemical, and genetic data of the 21 patients were subsequently reviewed. We reported 21 cases of PH in China, including 12 cases of PH1, 3 cases of PH2 and 6 cases of PH3, and identified 2 novel variants (c.632T > G and c.823_824del) in gene and 2 novel variants (c.258_272del and c.866-34_866-8del) in gene, respectively. A possible PH3 hotspot variant c.769T > G was identified for the first time. In addition, patients with PH1 showed higher levels of creatinine and lower eGFR than those with PH2 and PH3. In PH1, patients with severe variants in both alleles had significantly higher creatinine and lower eGFR than other patients. Delayed diagnosis still existed in some late-onset patients. Of all cases, 6 had reached to end-stage kidney disease (ESKD) at diagnosis with systemic oxalosis. Five patients were on dialysis and three had undergone kidney or liver transplants. Notably, four patients showed a favorable therapeutic response to vitamin B6, and c.823_824dup and c.145A > C may be identified as potentially vitamin B6-sensitive genotypes. In brief, our study identified 4 novel variants and extended the variant spectrum of PH in the Chinese population. The clinical phenotype was characterized by large heterogeneity, which may be determined by genotype and a variety of other factors. We first reported two variants that may be sensitive to vitamin B6 therapy in Chinese population, providing valuable references for clinical treatment. In addition, early screening and prognosis of PH should be given more attention. We propose to establish a large-scale registration system for rare genetic diseases in China and call for more attention on rare kidney genetic diseases.
PubMed: 37139236
DOI: 10.3389/fgene.2023.1124745 -
Frontiers in Medicine 2021Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that can result in irreversible damage to the kidneys and, eventually, extrarenal organs. While kidney...
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that can result in irreversible damage to the kidneys and, eventually, extrarenal organs. While kidney failure is a known consequence of PH1, few studies to date have characterized clinical consequences of PH1 prior to kidney failure, and data on healthcare resource use outcomes across different stages of disease severity in PH1 are also limited. To help fill this knowledge gap, this study characterized the clinical and healthcare resource use (HRU) burden in patients with PH1 with varying stages of kidney disease. Nephrologists in the United States, Canada, United Kingdom, France, Germany, and Italy abstracted chart data from patients with PH1 under their care via an online questionnaire. Eligible patients had confirmed PH1 and ≥2 office visits from 2016 to 2019. A total of 120 patients were analyzed (median age at diagnosis, 17.4 years old, median age at index 19.5 years old, median eGFR at index 45 ml/min/1.73 m; median follow-up 1.7 years). During follow-up, the most common PH1 manifestations were kidney stones and urinary tract infections (UTIs, both 56.8%), and the most common symptoms were fatigue/weakness (71.7%) and pain (64.6%). With regard to HRU during follow-up, 37.4% required lithotripsy, 31.3% required ureteroscopy, and 9.6% required nephrolithotomy. PH1-related hospitalizations and emergency/urgent care visits were noted for 84.0 and 81.6% of patients, respectively. The current study demonstrated that patients with PH1 across various stages of kidney disease exhibited a substantial clinical burden, including kidney stones, UTIs, fatigue/weakness, and pain, and required frequent HRU, including kidney stone procedures, hospitalizations, and emergency visits. These findings highlight the significant morbidity and HRU burden in patients with PH1.
PubMed: 34616753
DOI: 10.3389/fmed.2021.703305