-
Expert Opinion on Emerging Drugs Dec 2018: Currently, three types of primary hyperoxaluria (PH I-III) are known, all based on different gene-mutations affecting the glyoxylate metabolism in the liver. Disease... (Review)
Review
: Currently, three types of primary hyperoxaluria (PH I-III) are known, all based on different gene-mutations affecting the glyoxylate metabolism in the liver. Disease hallmark is an increased endogenous oxalate production and thus massively elevated urinary excretion of oxalate and other type-specific metabolites. Hyperoxaluria induces the formation of calcium-oxalate kidney stones and/or nephrocalcinosis. In addition to that, a chronic inflammasome activation by hyperoxaluria per se, often leads to an early deterioration of kidney function, regularly resulting in end-stage renal disease (ESRD) at least in patients with type I PH. Except for vitamin B6 treatment in PH I, therapeutic regimen nowadays consists only of supportive measures, like significantly increased fluid intake and medication increasing the urinary solubility like alkaline citrate. : Disease burden can be severe, and both clinicians and scientist are eager in finding new therapeutic approaches. The currently ongoing clinical studies and promising research in this field are reported in this paper. To present a complete overview, we searched electronic databases, like Clinical trial gov, National Center for Biotechnology Information PubMed, congress reports, press releases and personal information acquired at congresses and conventions. Searches were conducted using the following medical headings: (primary) hyperoxaluria, PH, therapy, treatment and research. : There is light on the horizon that new treatment options will be available in due time, as there are several promising therapeutic agents currently under investigation, some being at the first levels of drug development, but some already in ongoing clinical trials (phase I-III).
Topics: Animals; Carboxy-Lyases; Humans; Hyperoxaluria, Primary; Oxalobacter formigenes; RNA Interference
PubMed: 30540923
DOI: 10.1080/14728214.2018.1552940 -
Clinical Kidney Journal May 2022While the surgical approaches available in primary hyperoxaluria (PH) are common to all patients requiring intervention for urolithiasis, the indications for treatment... (Review)
Review
While the surgical approaches available in primary hyperoxaluria (PH) are common to all patients requiring intervention for urolithiasis, the indications for treatment and their corresponding toxicities are unique. Being a rare disease, we are guided by case series. This review summarizes the available literature highlighting the important disease-specific considerations. Shockwave lithotripsy (SWL) is of particular interest. It is generally the first-line treatment for stones in children, but here the stones produced will be relatively resistant to fragmentation. In addition, there are concerning reports in children of sudden unilateral decline in function in the treated kidney as measured by nuclear renography. Percutaneous nephrostolithotomy might intuitively seem favorable given the shortest drain duration and the ability to treat larger stones efficiently but, similar to SWL, rapid chronic kidney disease (CKD) progression has been seen postoperatively. Ureteroscopy is therefore generally the safest option, but considerations regarding stent encrustation, the growth of residual fragments and the large volume of stone often faced may limit this approach. The surgeon must balance the above with consideration of the patient's CKD status when considering a plan of monitoring and treating stones in PH.
PubMed: 35592623
DOI: 10.1093/ckj/sfab187 -
Pediatric Nephrology (Berlin, Germany) Sep 2021Loss-of-function mutations in three genes, involved in the metabolic pathway of glyoxylate, result in increased oxalate production and its crystallization in the form of... (Review)
Review
Loss-of-function mutations in three genes, involved in the metabolic pathway of glyoxylate, result in increased oxalate production and its crystallization in the form of calcium oxalate. This leads to three forms of primary hyperoxaluria-an early-onset inherited kidney disease with wide phenotypic variability ranging from isolated kidney stone events to stage 5 chronic kidney disease in infancy. This review provides a description of metabolic processes resulting in oxalate overproduction and summarizes basic therapeutic approaches. Unfortunately, current treatment of primary hyperoxaluria does not allow the prevention of loss of kidney function or to substantially diminish other symptoms in most patients. However, latest breakthroughs in biotechnology provide new promising directions for drug development. Some of them have already progressed to the level of clinical trials; others are just at the stage of proof of concept. Here we review the most advanced technologies including those that have been harnessed as possible therapeutic modalities.
Topics: Humans; Hyperoxaluria, Primary
PubMed: 33156410
DOI: 10.1007/s00467-020-04817-8 -
Ophthalmology. Retina Sep 2020
Topics: Humans; Hyperoxaluria, Primary; Infant; Macula Lutea; Macular Degeneration; Oxalates
PubMed: 32896362
DOI: 10.1016/j.oret.2020.04.008 -
Nature Reviews. Urology Mar 2022Primary hyperoxalurias are a devastating family of diseases leading to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease.... (Review)
Review
Primary hyperoxalurias are a devastating family of diseases leading to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease. Traditional treatment paradigms are limited to conservative management, dialysis and combined transplantation of the kidney and liver, of which the liver is the primary source of oxalate production. However, transplantation is associated with many potential complications, including operative risks, graft rejection, post-transplant organ failure, as well as lifelong immunosuppressive medications and their adverse effects. New therapeutics being developed for primary hyperoxalurias take advantage of biochemical knowledge about oxalate synthesis and metabolism, and seek to specifically target these pathways with the goal of decreasing the accumulation and deposition of oxalate in the body.
Topics: Female; Humans; Hyperoxaluria, Primary; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Oxalates
PubMed: 34880452
DOI: 10.1038/s41585-021-00543-4 -
Current Opinion in Nephrology and... Jul 2022Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that causes hepatic overproduction of oxalate and, often, nephrocalcinosis, nephrolithiasis, chronic kidney... (Review)
Review
PURPOSE OF REVIEW
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that causes hepatic overproduction of oxalate and, often, nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. The purpose of the review is to provide an update on current emerging therapies for the treatment of PH1.
RECENT FINDINGS
Use of ribonucleic acid interference (RNAi) therapeutics that target the liver to block production of key enzymes along pathways that generate oxalate is a promising approach. Available evidence supports the efficacy of both Lumasiran (targeting glycolate oxidase) and Nedosiran (targeting hepatic lactate dehydrogenase (LDHa)) to reduce urinary oxalate excretion in PH1. The efficacy of alternative approaches including stiripentol (an anticonvulsant drug that also targets LDHa), lanthanum (a potential gastrointestinal oxalate binder), and Oxalobacter formigenes (a bacterium that can degrade oxalate within the gastrointestinal tract and may also increase its secretion from blood) are all also under study. Genetic editing tools including clustered regularly interspaced short palindromic repeats/Cas9 are also in preclinical study as a potential PH1 therapeutic.
SUMMARY
Novel treatments can reduce the plasma oxalate concentration and urinary oxalate excretion in PH1 patients. Thus, it is possible these approaches will reduce the need for combined kidney and liver transplantation to significantly decrease the morbidity and mortality of affected patients.
Topics: Humans; Hyperoxaluria, Primary; Kidney Calculi; L-Lactate Dehydrogenase; Oxalates; RNA, Small Interfering
PubMed: 35266883
DOI: 10.1097/MNH.0000000000000790 -
Genes Aug 2023Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet,... (Review)
Review
Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet, microbiota, renal and metabolic disease) reasons underlie elevated plasma concentrations and tissue accumulation of oxalate, which is toxic to the body. A classic example is the triad of primary hyperoxaluria, nephrolithiasis, and kidney injury. Lessons learned from this example suggest further investigation of other putative factors associated with oxalate dysmetabolism, namely the identification of precursors (glyoxylate, aromatic amino acids, glyoxal and vitamin C), the regulation of the endogenous pathways that produce oxalate, or the microbiota's contribution to oxalate systemic availability. The association between secondary nephrolithiasis and cardiovascular and metabolic diseases (hypertension, type 2 diabetes, and obesity) inspired the authors to perform this comprehensive review about oxalate dysmetabolism and its relation to cardiometabolic toxicity. This perspective may offer something substantial that helps advance understanding of effective management and draws attention to the novel class of treatments available in clinical practice.
Topics: Humans; Oxalates; Diabetes Mellitus, Type 2; Hyperoxaluria, Primary; Kidney; Nephrolithiasis; Hypertension
PubMed: 37761859
DOI: 10.3390/genes14091719 -
Pediatric Nephrology (Berlin, Germany) Aug 2023Primary hyperoxaluria (PH) results from genetic mutations in different genes of glyoxylate metabolism, which cause significant increases in production of oxalate by the... (Observational Study)
Observational Study
BACKGROUND
Primary hyperoxaluria (PH) results from genetic mutations in different genes of glyoxylate metabolism, which cause significant increases in production of oxalate by the liver. This study aimed to report clinical and laboratory manifestations and outcome of PH type 1 in children in our center.
METHODS
A single-center observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients admitted from 2018 to 2020, with a diagnosis of hyperoxaluria (urinary oxalate excretion > 45 mg/1.73 m/day, or > 0.5 mmol/1.73 m/day). PH type 1 (PH1) diagnosis was established by identification of biallelic pathogenic variants (compound heterozygous or homozygous mutations) in AGXT gene on molecular genetic testing.
RESULTS
The study included 100 patients with hyperoxaluria, with slight male dominance (57%), and median age 1.75 years (range, 1 month-14 years). Initial complaint was urolithiasis or nephrocalcinosis in 47%, kidney failure manifestations in 29%, and recurrent urinary tract infection in 24%. AGXT mutations were detected in 40 patients, and 72.5% of PH1 patients had kidney failure at presentation. Neither gender, age nor urinary oxalate excretion in 24 h had statistical significance in distinguishing PH1 from other forms of hyperoxaluria (P-Value > 0.05). Parental consanguinity, family history of kidney stones, bilateral nephrocalcinosis, presence of oxalate crystals in random urine sample, kidney failure and mortality were statistically significantly higher in PH1 (P-values < 0.05). Mortality was 32.5% among PH1 patients, with 4 PH1 patients (10%) on hemodialysis awaiting combined liver-kidney transplantation.
CONCLUSION
PH1 is still a grave disease with wide variety of clinical presentations which frequent results in delays in diagnosis, thus kidney failure is still a common presentation. In Syria, we face many challenges in diagnosis of PH, especially PH2 and PH3, and in management, with hopes that diagnosis tools and modern therapies will become available in our country. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Child; Humans; Male; Infant; Nephrocalcinosis; Hyperoxaluria, Primary; Oxalates; Hyperoxaluria; Kidney Calculi; Renal Insufficiency
PubMed: 36917293
DOI: 10.1007/s00467-023-05917-x -
Clinical Kidney Journal May 2022The clinical presentation of primary hyperoxaluria in children ranges from mildly symptomatic nephrocalcinosis to very early onset end-stage kidney failure with systemic... (Review)
Review
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.
PubMed: 35592624
DOI: 10.1093/ckj/sfab231 -
International Journal of Surgery... Dec 2016Renal stones are common and are usually secondary to risk factors affecting the solubility of substances in the urinary tract. Primary, that is genetic, causes are rare... (Review)
Review
Renal stones are common and are usually secondary to risk factors affecting the solubility of substances in the urinary tract. Primary, that is genetic, causes are rare but nevertheless are important to recognise so that appropriate treatments can be instigated and the risks to other family members acknowledged. A brief overview of the investigation of renal stones from a biochemical point of view is presented with emphasis on the problems that can arise. The genetic basis of renal stone disease caused by (i) derangement of a metabolic pathway, (ii) diversion to an insoluble product, (iii) failure of transport and (iv) renal tubular acidosis is described by reference to the disorders of adenine phosphoribosyl transferase (APRT) deficiency, primary hyperoxaluria, cystinuria and autosomal dominant distal renal tubular acidosis.
Topics: Acidosis, Renal Tubular; Adenine Phosphoribosyltransferase; Adult; Genetic Predisposition to Disease; Humans; Hyperoxaluria, Primary; Kidney Calculi; Metabolism, Inborn Errors; Urolithiasis
PubMed: 27838384
DOI: 10.1016/j.ijsu.2016.11.015