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Pediatric Nephrology (Berlin, Germany) Dec 2018Combined and sequential liver-kidney transplantation (CLKT and SLKT) is a definitive treatment in children with end-stage organ failure. There are two major indications:... (Review)
Review
Combined and sequential liver-kidney transplantation (CLKT and SLKT) is a definitive treatment in children with end-stage organ failure. There are two major indications: - terminal insufficiency of both organs, or - need for transplanting new liver as a source of lacking enzyme or specific regulator of the immune system in a patient with renal failure. A third (uncommon) option is secondary end-stage renal failure in liver transplant recipients. These three clinical settings use distinct qualification algorithms. The most common indications include primary hyperoxaluria type 1 (PH1) and autosomal recessive polycystic kidney disease (ARPKD), followed by liver diseases associated with occasional kidney failure. Availability of anti-C5a antibody (eculizumab) has limited the validity of CLKT in genetic atypical hemolytic uremic syndrome (aHUS). The liver coming from the same donor as renal graft (in CLKT) is immunologically protective for the kidney and this provides long-term rejection-free follow-up. No such protection is observed in SLKT, when both organs come from different donors, except uncommon cases of living donation of both organs. Overall long-term outcome in CLKT in terms of graft survival is good and not different from isolated liver or kidney transplantation, however patient survival is inferior due to complexity of this procedure.
Topics: Atypical Hemolytic Uremic Syndrome; Child; End Stage Liver Disease; Graft Rejection; Graft Survival; Humans; Hyperoxaluria, Primary; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Polycystic Kidney, Autosomal Recessive; Survival Analysis; Tissue and Organ Procurement; Transplantation, Homologous; Treatment Outcome
PubMed: 29322327
DOI: 10.1007/s00467-017-3880-4 -
Journal of Medical Case Reports Oct 2023Primary hyperoxaluria (PH) is a rare genetic disorder characterized by the excessive production and accumulation of oxalate. We present five cases of PH, each exhibiting...
BACKGROUND
Primary hyperoxaluria (PH) is a rare genetic disorder characterized by the excessive production and accumulation of oxalate. We present five cases of PH, each exhibiting varying manifestations of the disorder including a case presenting as postpartum kidney failure. Notably, three of these cases involve a previously unreported mutation.
CASE PRESENTATIONS
We evaluated five Indian patients who presented with varying manifestations of PH. The first case, a 30 year old woman, presented as post-partum kidney failure and was found to be having oxalate nephropathy precipitated by dietary oxalate overload in the setting of previously undiagnosed PH. Genetic analysis revealed a previously unreported mutation in the alanine-glyoxylate aminotransferase gene. The patient underwent simultaneous kidney liver transplant. The second and third cases, 26 and 28 year old women respectively, were asymptomatic siblings of the first patient, who were diagnosed through screening. The fourth case is a 12 year boy with PH type 1 presenting as nephrolithiasis and rapidly worsening kidney function requiring combined kidney liver kidney transplant. Case 5 is a 6 year old male child with type 2 PH presenting with nephrolithiasis, nephrocalcinosis and normal kidney function. All the patients were born to consanguineous parents.
CONCLUSIONS
Due to limited clinical suspicion and inadequate diagnostic resources in certain countries with limited resources, it is possible for PH to go undiagnosed. The manifestations of the disease can range from no noticeable symptoms to severe disease. Interestingly, in some individuals with primary hyperoxaluria, the disease may not exhibit any symptoms until it is triggered by a high intake of dietary oxalate.
Topics: Male; Child; Humans; Female; Adult; Hyperoxaluria, Primary; Kidney; Oxalates; Kidney Calculi; Renal Insufficiency
PubMed: 37803380
DOI: 10.1186/s13256-023-04129-z -
Pediatric Nephrology (Berlin, Germany) Apr 2023Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate....
BACKGROUND
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018-004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here.
METHODS
Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7-20.5) months).
RESULTS
Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)).
CONCLUSIONS
Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Child; Child, Preschool; Humans; Infant; Hyperoxaluria, Primary; Kidney Calculi; Oxalates
PubMed: 35913563
DOI: 10.1007/s00467-022-05684-1 -
Pediatric Nephrology (Berlin, Germany) Mar 2023Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial... (Review)
Review
Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis.
Topics: Humans; Hyperoxaluria, Primary; Pyridoxine; Mutation; Genetic Testing; Genotype; Transaminases
PubMed: 35695965
DOI: 10.1007/s00467-022-05613-2 -
Nephrologie & Therapeutique Nov 2016Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxalate and oxalate with recessive autosomal transmission. As a result, an increased endogenous... (Review)
Review
Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxalate and oxalate with recessive autosomal transmission. As a result, an increased endogenous production of oxalate leads to exessive urinary oxalate excretion. PH type 1, the most common form, is due to a deficiency of the peroxisomal enzyme alanine: Glyoxylate aminotransferase (AGT) in the liver. PH type 2 is due to the deficiency of the glyoxylate reductase/hydroxypyruvate réductase, present in the cytosol of hepatocytes and leucocytes. PH type 3 is linked to the gene HOGA1, encoding a mitochondrial enzyme, the 4-hydroxy-2-oxo-glutarate aldolase. Recurrent urolithiaisis and nephrocalcinosis are the markers of the disease. As a result, a progressive dysfunction of the kidneys is commonly observed. At the stage of severe chronic kidney disease, plasma oxalate increase leads to a systemic oxalosis. Diagnostic is often delayed and it based on stone analysis, cristalluria, oxaluria determination and DNA analysis. Early initiation of conservative treatment including high fluid intake and long-term co-administration of inhibitors of calcium oxalate crystallization and pyridoxine, could efficiently prevent end stage renal disease. In end stage renal failure, a combined liver-kidney transplantation corrects the enzyme defect.
Topics: Disease Progression; Fluid Therapy; Humans; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Nephrocalcinosis; Peritoneal Dialysis; Treatment Outcome; Vitamin B 6; Vitamin B Complex
PubMed: 27372182
DOI: 10.1016/j.nephro.2016.03.005 -
Urolithiasis Oct 2023Based on the single-center case reports and all reported patients with primary hyperoxaluria type 1 (PH1) in China, this study discussed the clinical and genetic...
Based on the single-center case reports and all reported patients with primary hyperoxaluria type 1 (PH1) in China, this study discussed the clinical and genetic characteristics of this disease retrospectively. We reported and validated a novel genetic variation c.302 T > G: the clinical phenotypes of the two siblings were similar, in which both had onset in infancy, mainly manifested as renal insufficiency, and died within 6 months out of end-stage renal disease. The literature review is the first to summarize the Chinese patients with PH1 up to now. Forty-eight Chinese patients were included, containing 7 adults and 41 children. The median onset age was 51 months, and the ratio of male to female was 2.69:1. It showed a poor prognosis: 51.1% of Chinese primary hyperoxaluria type 1 patients suffered from end-stage renal disease, and 38.9% of patients died. Urolithiasis was the most common clinical manifestation both in adults and children, while infant-onset patients generally presented with renal insufficiency and had a higher mortality of 75.0%. One hundred and forty-nine AGXT mutant alleles are currently known in the Chinese population, c.33dupC and c.815_816insGA were the most common AGXT genes, accounting for 12.0% and 10.1% of allele frequencies, respectively. The exons 1, 2, 6, and 8 were the most common locations of gene variants, accounting for 78% of all variants, which will be promising targets of DNA sequencing for primary hyperoxaluria type 1.
Topics: Adult; Child; Child, Preschool; Female; Humans; Infant; Male; East Asian People; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Failure, Chronic; Mutation; Retrospective Studies
PubMed: 37874369
DOI: 10.1007/s00240-023-01494-8 -
Urolithiasis Feb 2019Primary hyperoxalurias (PHs) are rare inherited disorders of liver glyoxylate metabolism, characterized by the abnormal production of endogenous oxalate, a metabolic... (Review)
Review
Primary hyperoxalurias (PHs) are rare inherited disorders of liver glyoxylate metabolism, characterized by the abnormal production of endogenous oxalate, a metabolic end-product that is eliminated by urine. The main symptoms are related to the precipitation of calcium oxalate crystals in the urinary tract with progressive renal damage and, in the most severe form named Primary Hyperoxaluria Type I (PH1), to systemic oxalosis. The therapies currently available for PH are either poorly effective, because they address the symptoms and not the causes of the disease, or highly invasive. In the last years, advances in our understanding of the molecular bases of PH have paved the way for the development of new therapeutic strategies. They include (i) substrate-reduction therapies based on small-molecule inhibitors or the RNA interference technology, (ii) gene therapy, (iii) enzyme administration approaches, (iv) colonization with oxalate-degrading intestinal microorganisms, and, in PH1, (v) design of pharmacological chaperones. This paper reviews the basic principles of these new therapeutic strategies and what is currently known about their application to PH.
Topics: Alcohol Oxidoreductases; Calcium Oxalate; Gastrointestinal Microbiome; Genetic Therapy; Glyoxylates; Humans; Hyperoxaluria, Primary; Kidney; Kidney Transplantation; Liver; Liver Transplantation; Nephrolithiasis; Oxalobacter formigenes; Pyridoxine; RNA Interference; Renal Elimination; Transaminases; Treatment Outcome
PubMed: 30430197
DOI: 10.1007/s00240-018-1089-z -
Journal of the American Society of... Jun 2018Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The...
Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known. To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [N,C]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary C-oxalate and C-glycolate formed using ion chromatography coupled to mass detection. The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and <13% in subjects with PH2 or PH3. Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.
Topics: Adult; Creatinine; Female; Glycolates; Humans; Hydroxyproline; Hyperoxaluria, Primary; Male; Middle Aged; Oxalic Acid; Young Adult
PubMed: 29588429
DOI: 10.1681/ASN.2017040390 -
Clinical Kidney Journal May 2022Primary hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disease of oxalate metabolism, resulting from a mutation in the gene that encodes the... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disease of oxalate metabolism, resulting from a mutation in the gene that encodes the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). Until recently, treatment of PH1 was supportive, consisting of intensive hyperhydration, use of crystallization inhibitors (citrate and neutral phosphorus), in a subset of responsive PH1 patients' pharmacologic doses of vitamin B6 (pyridoxine), and kidney and liver transplantation when patients progressed to kidney failure. Treatment approaches have been similar for PH2 caused by mutations in hepatic glyoxylate reductase/hydroxypyruvate reductase (), although pyridoxine does not have any benefit in this group. PH3 is caused by mutations of mitochondrial 4-hydroxy-2-oxoglutarate aldolase () and was the most recently described. Kidney failure appears less common in PH3, although kidney stones occur as frequently as in PH1 and PH2. Oxalate metabolism in the liver is complex. Novel therapies based on RNA interference (RNAi) have recently emerged to modulate these pathways, designed to deplete substrate for enzymes upstream and decrease/avoid oxalate production. Two hepatic enzymes have been targeted to date in PH: glycolate oxidase (GO) with lumasiran and lactate dehydrogenase A (LDH-A) with nedosiran. Lumasiran was approved for the treatment of PH1 in 2020 by both the European Medicines Agency and the Food and Drug Administration, whilst clinical trials with nedosiran are ongoing. Results with the two RNAi therapies demonstrate a significant reduction of urinary oxalate excretion in PH1 patients, but long-term data on efficacy (preservation of kidney function, decreased stone events) and safety remain to be established. Nevertheless, the hepatically targeted RNAi approach represents a potential 'game changer' in the field of PH1, bringing hope to families and patients that they may be able to avoid liver and/or kidney transplantation in the future and suffer fewer stone events, perhaps with less strict therapeutic regimens. Pharmacological compounds directly inhibiting GO or LDH are also under development and could be of special interest in developing countries where RNAi therapies may not be readily available in the near future. Approaches to manipulate the intestinal microbiome with a goal to increase oxalate degradation or to stimulate secretion of oxalate into the intestine from plasma are also under development. Overall, we appear to be entering a new phase of PH treatment, with an array of promising approaches emerging that will need optimization and evaluation to establish long-term efficacy and safety.
PubMed: 35592618
DOI: 10.1093/ckj/sfab245 -
Urolithiasis Feb 2019Primary hyperoxaluria (PH) is caused by genetic mutations resulting in oxalate overproduction leading to nephrolithiasis, nephrocalcinosis, extrarenal manifestations,... (Review)
Review
Primary hyperoxaluria (PH) is caused by genetic mutations resulting in oxalate overproduction leading to nephrolithiasis, nephrocalcinosis, extrarenal manifestations, chronic kidney disease, and end-stage renal disease. Advances in genetic testing techniques have improved our ability to efficiently and effectively obtain a definitive diagnosis of PH as well as easily screen at-risk family members. Similarly, advances in technologies related to intervening at the genetic and molecular level promise to change the way we treat patients with PH. In this review, we provide an update regarding the identification of underlying molecular and biochemical causes of inherited hyperoxalurias, clinical manifestations, and treatment strategies.
Topics: Alcohol Oxidoreductases; Fluid Therapy; Genetic Testing; Humans; Hyperoxaluria, Primary; Kidney Calculi; Kidney Transplantation; Lithotripsy; Liver Transplantation; Mutation; Nephrocalcinosis; Oxalates; Oxo-Acid-Lyases; Pyridoxine; Renal Replacement Therapy; Transaminases; Treatment Outcome
PubMed: 30535828
DOI: 10.1007/s00240-018-1093-3