Materiały źródłowe

• #1 Hyperoxaluria – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK558987/

  Hyperoxaluria is a significant contributor to nephrolithiasis, and the causes of excess urinary oxalate can be classified based on etiology into primary and secondary hyperoxaluria. […] Even relatively small changes in urinary oxalate can have a very significant impact on kidney stone production. In addition, the presence of hyperoxaluria alone, without concurrent nephrolithiasis, also has deleterious effects on the kidney, resulting in fibrosis, acute kidney injury, and tubular atrophy. […] Hyperoxaluria can be broadly divided into primary (rare) and secondary (common). […] Primary Hyperoxaluria (PH) is caused by an inherent genetic defect or absence of a specific enzymatic activity, ultimately leading to significantly increased oxalate levels in the body. […] Symptoms typically appear in childhood, with a median age of presentation of only 4 to 5 years old.

• #1 Hyperoxaluria – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK558987/

  PH often leads to multiple recurrent calcium oxalate nephrolithiasis episodes, nephrocalcinosis, and progressive renal damage, which may become end-stage renal disease (ESRD). […] The crystallization and deposition of calcium oxalate within the renal parenchymal tissues is known as nephrocalcinosis. Together, these 2 processes of nephrocalcinosis and calcium oxalate stone formation will cause inflammation and progressive renal injury that eventually can lead to a decline in renal function and, ultimately, ESRD. […] Oxalate alone can also crystallize in the kidney, leading to obstruction, interstitial fibrosis, tubular toxicity, and atrophy. […] The Chronic Renal Insufficiency Cohort (CRIC) study was a large, multicenter prospective study that found that higher 24-hour urine oxalate excretion was likely independently associated with increased chronic kidney disease (CKD) and ESRD. […] Oxalate nephropathy has a poor prognosis, with 40% to 50% of cases resulting in ESRD. […] The prognosis of hyperoxaluria depends on the type of hyperoxaluria, time of diagnosis, and early initiation of treatment, amongst other things.

• #2 Primary and secondary hyperoxaluria: Understanding the enigma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4419133/

  Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria is an inherited error of metabolism due to defective enzyme activity. In contrast, secondary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease. When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in various organ systems in a process called systemic oxalosis. Increased urinary oxalate levels help to make the diagnosis while plasma oxalate levels are likely to be more accurate when patients develop chronic kidney disease. Definitive diagnosis of primary hyperoxaluria is achieved by genetic studies and if genetic studies prove inconclusive, liver biopsy is undertaken to establish diagnosis. Diagnostic clues pointing towards secondary hyperoxaluria are a supportive dietary history and tests to detect increased intestinal absorption of oxalate. Conservative treatment for both types of hyperoxaluria includes vigorous hydration and crystallization inhibitors to decrease calcium oxalate precipitation. Pyridoxine is also found to be helpful in approximately 30% patients with primary hyperoxaluria type 1. Liver-kidney and isolated kidney transplantation are the treatment of choice in primary hyperoxaluria type 1 and type 2 respectively. Data is scarce on role of transplantation in primary hyperoxaluria type 3 where there are no reports of end stage renal disease so far. There are ongoing investigations into newer modalities of diagnosis and treatment of hyperoxaluria. Clinical differentiation between primary and secondary hyperoxaluria and further between the types of primary hyperoxaluria is very important because of implications in treatment and diagnosis. Hyperoxaluria continues to be a challenging disease and a high index of clinical suspicion is often the first step on the path to accurate diagnosis and management.

• #3 Hyperoxaluria and oxalosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hyperoxaluria/symptoms-causes/syc-20352254

  Hyperoxaluria (hi-pur-ok-suh-LU-ree-uh) happens when you have too much oxalate in your urine. […] Hyperoxaluria can be caused by a change in a gene, an intestine disease or eating too many foods that are high in oxalate. […] Oxalosis (ok-suh-LOW-sis) happens after the kidneys stop working well in people who have primary and intestine-related causes of hyperoxaluria. Too much oxalate collects in the blood. This can lead to oxalate buildups in blood vessels, bones and organs. […] Hyperoxaluria happens when too much of a chemical called oxalate builds up in the urine. […] Primary hyperoxaluria. This type is a rare inherited disease, which means that it’s passed down in families. It’s caused by changes in a gene. With primary hyperoxaluria, the liver doesn’t make enough of a certain protein that prevents too much oxalate from being made. Or the protein doesn’t work as it should. The body gets rid of excess oxalate through the kidneys, in urine. The extra oxalate can combine with calcium to form kidney stones and crystals. These can damage the kidneys and cause them to stop working.

• #3 Hyperoxaluria and oxalosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hyperoxaluria/symptoms-causes/syc-20352254

  With primary hyperoxaluria, kidney stones form early. They most often cause symptoms from childhood through age 20. The kidneys of many people with primary hyperoxaluria stop working well by early to middle adulthood. But kidney failure can happen even in babies with this disease. Others with primary hyperoxaluria may never have kidney failure. […] Enteric hyperoxaluria. Some intestine problems cause the body to absorb more oxalate from foods. This can then increase the amount of oxalate in the urine. Crohn’s disease is one intestine problem that can lead to enteric hyperoxaluria. Another is short bowel syndrome, which can happen when parts of the small intestine are removed during surgery. […] Oxalosis happens if you have primary or enteric hyperoxaluria and your kidneys stop working well enough. The body can no longer get rid of the extra oxalate, so the oxalate starts building up. First it builds up in the blood, then in the eyes, bones, skin, muscles, blood vessels, heart and other organs. […] Oxalosis can cause many health problems outside the kidneys in its late stages.

• #4 Primary and secondary hyperoxaluria: Understanding the enigma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4419133/

  The causes of SH are increase in dietary and intestinal absorption (enteric hyperoxaluria), excessive intake of oxalate precursors and alteration in intestinal microflora. […] Oxalate is a product of ethylene glycol causing calcium oxalate deposition and renal failure. Hyperoxaluria has also been reported following renal transplantation due to mobilization of oxalate and deposition within the renal allograft. Increased intestinal absorption of oxalate and tubular secretion has also been reported in patients with cystic fibrosis leading to hyperoxaluria. […] The prevalence of PH1 is approximately 1-3 cases per million population. At least 1% of the ESRD seen in the pediatric population is attributable to PH1 in European and Japanese studies. It is more frequently seen in Kuwaiti and Tunisian populations where consanguineous marriages are practiced. PH1 is the most severe type of PH although there is significant variability in its clinical presentation. Patients may present early in life during infancy with life threatening oxalosis and failure to thrive or in adulthood after passing an occasional stone. Overall, the disease is characterized by recurrent nephrolithiasis and progressive nephrocalcinosis leading to renal damage and as a result, the majority of the patients reach ESRD during 3rd-5th decade of life.

• #4 Primary and secondary hyperoxaluria: Understanding the enigma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4419133/

  Patients with secondary hyperoxaluria have a predisposition to developing recurrent calcium oxalate stones due to the underlying disorder. This leads to worsening renal damage and progression to ESRD. Systemic oxalosis is less common in secondary hyperoxaluria but reported in some severe cases of Crohns disease. […] Calcium oxalate salts are poorly soluble in body fluids. Calcium oxalate deposits within renal tissue as nephrocalcinosis and also forms renal stones (nephrolithiasis). This leads to progressive renal injury and inflammation and tubular obstruction leading to interstitial fibrosis, declining renal function and eventually ESRD. […] When glomerular filtration rate (GFR) drops below 30-40 mL/min per 1.73 m2, renal capacity to excrete calcium oxalate is significantly impaired. At this stage, calcium oxalate starts to deposit in extra renal tissues in a process called systemic oxalosis. Calcium oxalate deposits have been reported in the myocardium, cardiac conduction system, kidneys, bones and bone marrow. This leads to cardiomyopathy, heart block and other cardiac conduction defects, vascular disease, retinopathy, synovitis, oxalate osteopathy and anemia that is noted to be resistant to treatment.

• #4 Primary and secondary hyperoxaluria: Understanding the enigma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4419133/

  Diagnosis of hyperoxaluria is established using a combination of clinical, radiological, biochemical, histopathological and genetic studies in primary hyperoxaluria. Precise diagnosis is of paramount importance for prognostic and treatment implications and also for prenatal screening in appropriate cases where PH is suspected. […] In patients with a clinical suspicion for hyperoxaluria, the diagnostic workup should begin with ultrasound or other radiological imaging of the kidneys and the rest of the urinary tract to confirm the presence of nephrocalcinosis and urolithiasis. Stone analysis should be done and may yield the initial diagnostic clues for PH. Stones in PH are composed of monohydrate calcium oxalate (whewellite) which assume a dumbbell shaped form. […] Non-invasive, definitive diagnosis of PH is provided by testing of AGXT, GRHPR and HOGA1 genes. There are 150 known mutations for AGXT, 16 for GRHP and 15 for HOGA1.

• #4 Primary and secondary hyperoxaluria: Understanding the enigma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4419133/

  Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria is an inherited error of metabolism due to defective enzyme activity. In contrast, secondary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease. When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in various organ systems in a process called systemic oxalosis. Increased urinary oxalate levels help to make the diagnosis while plasma oxalate levels are likely to be more accurate when patients develop chronic kidney disease. Definitive diagnosis of primary hyperoxaluria is achieved by genetic studies and if genetic studies prove inconclusive, liver biopsy is undertaken to establish diagnosis. Diagnostic clues pointing towards secondary hyperoxaluria are a supportive dietary history and tests to detect increased intestinal absorption of oxalate. Conservative treatment for both types of hyperoxaluria includes vigorous hydration and crystallization inhibitors to decrease calcium oxalate precipitation. Pyridoxine is also found to be helpful in approximately 30% patients with primary hyperoxaluria type 1. Liver-kidney and isolated kidney transplantation are the treatment of choice in primary hyperoxaluria type 1 and type 2 respectively. Data is scarce on role of transplantation in primary hyperoxaluria type 3 where there are no reports of end stage renal disease so far. There are ongoing investigations into newer modalities of diagnosis and treatment of hyperoxaluria. Clinical differentiation between primary and secondary hyperoxaluria and further between the types of primary hyperoxaluria is very important because of implications in treatment and diagnosis. Hyperoxaluria continues to be a challenging disease and a high index of clinical suspicion is often the first step on the path to accurate diagnosis and management.

• #4 Primary and secondary hyperoxaluria: Understanding the enigma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4419133/

  Transplantation must be planned when GFR falls between 15-30 mL/min per 1.73 m2. As the defective enzyme is liver specific in PH1, these patients require preemptive liver, sequential liver- kidney, or combined liver-kidney transplantation. Transplantation strategy is decided based on individual presentation and clinical course as disease expression may vary among patients with PH1.

• #5 Hyperoxaluria: Practice Essentials, Oxalate Production and Function, Pathophysiology and Etiology

  https://emedicine.medscape.com/article/444683-overview

  In type 2 primary hyperoxaluria the missing enzyme is glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which can be detected in leukocyte preparations. This deficiency promotes the conversion of glyoxylate to oxalate. […] Type 3 primary hyperoxaluria is due to mutations in the HOGA1 (formerly DHDPSL) gene. Research supports a loss-of-function mechanism, resulting in a build-up of 4-hydroxy-2-oxoglutarate and/or its metabolites in mitochondria with subsequent leakage into the cytosol, where it can be converted to glyoxylate. […] Enteric hyperoxaluria accounts for approximately 5% of all cases of hyperoxaluria. It is due to a gastrointestinal problem usually associated with chronic diarrhea. Malabsorption from any cause can result in enteric hyperoxaluria. […] The basic mechanism is competition for the available ingested calcium, the leading intestinal oxalate-binding agent.

• #5 Hyperoxaluria: Practice Essentials, Oxalate Production and Function, Pathophysiology and Etiology

  https://emedicine.medscape.com/article/444683-overview

  Increased intestinal membrane oxalate transport and absorption may also occur through direct exposure of the intestinal lining to excess bile salts and fatty acids, which increases the oxalate permeability of the colonic mucosa. […] Dietary oxalate was thought to play a relatively minor role in hyperoxaluria and to account for only 10-20% of the total urinary oxalate produced. More recent evidence suggests that dietary oxalate plays a much more important role and may be responsible for 50% of the total urinary oxalate. […] Many patients, perhaps as many as 80%, have an abnormal or altered cellular membrane oxalate transport mechanism, which causes abnormally high absorption of dietary oxalate. […] Oxalate is involved in various metabolic and homeostatic mechanisms in fungi and bacteria and may play an important role in various aspects of animal metabolism, including mitochondrial activity regulation, thyroid function, gluconeogenesis, and glycolysis.

• #5 Hyperoxaluria: Practice Essentials, Oxalate Production and Function, Pathophysiology and Etiology

  https://emedicine.medscape.com/article/444683-overview

  In humans, however, oxalate seems to have no substantially beneficial role and acts as a metabolic end-product, much like uric acid. If not for oxalate’s high affinity for calcium and the low solubility of calcium oxalate, oxalate and oxalate metabolism would be of little interest. Urinary oxalate is the single strongest chemical promoter of kidney stone formation.

• #6 Primary hyperoxaluria – UpToDate

  https://www.uptodate.com/contents/primary-hyperoxaluria

  It is the most common PH type and accounts for approximately 70 to 80 percent of PH cases. […] It is the most severe form of PH, with more rapid progression to kidney dysfunction and the development of ESKD in one-half of patients by young adulthood. […] More than 190 variants have been identified in the AGXT gene, which are found in all 11 exons of the gene. […] The variants, most of which lead to a major or complete loss of enzyme activity, are predominantly single nucleotide substitutions including missense, nonsense, and splice site mutations, and the remaining variants are due to deletions and insertions.

• #6 Primary hyperoxaluria – UpToDate

  https://www.uptodate.com/contents/primary-hyperoxaluria

  Primary hyperoxalurias (PHs) are rare inborn errors of glyoxylate metabolism characterized by the overproduction of oxalate, which is poorly soluble and is deposited as calcium oxalate in various organs. […] These pathologic variants result in enhanced oxalate production. […] As oxalate is typically excreted in the urine, the kidney is the prime target for excessive oxalate deposition resulting in nephrocalcinosis and kidney stones and, in some cases, end-stage kidney disease (ESKD). […] PH type 1 (MIM #259900) is due to variants of AGXT that encodes the hepatic peroxisomal enzyme alanine glyoxylate aminotransferase (AGT), a pyridoxal 5′-phosphate-dependent enzyme, which is involved in the transamination of glyoxylate to glycine. […] This inborn error of metabolism leads to an increase in the glyoxylate pool, which is converted by lactate dehydrogenase to oxalate.

• #7 Lumasiran for Primary Hyperoxaluria Type 1

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/lumasiran-for-primary-hyperoxaluria-type-1/

  Primary hyperoxaluria is a rare disorder of glyoxylate metabolism characterized by the overproduction of oxalate, which is poorly soluble and deposited as calcium oxalate in the kidneys and urinary tract, leading to the formation of painful and recurrent nephrolithiasis (renal stones), nephrocalcinosis, and renal failure. Compromised renal function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. […] There are 3 types of primary hyperoxaluria. Each of these is caused by a defect in a gene that governs the production of a different hepatic enzyme, and each results in the overproduction of oxalate by the liver. The 3 types are summarized in Table 1. Type 1 is the most common type, which accounts for approximately 80% of cases. Homozygous or compound heterozygous alanine:glyoxylate aminotransferase (AGXT) variants lead to hepatic deficiency of alanine glyoxalate aminotransferase, which converts glyoxalate into pyruvate and glycine. Absent or deficient levels lead to accumulation of oxalate and its deposition as calcium oxalate.

• #7 Lumasiran for Primary Hyperoxaluria Type 1

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/lumasiran-for-primary-hyperoxaluria-type-1/

  Diagnosis of primary hyperoxaluria type 1 is often delayed because of the rarity of the condition and general lack of awareness of the disease. Diagnosis generally involves 3 steps: Clinical suspicion based on symptoms and radiographic features such as recurrent renal stones, nephrocalcinosis associated with decreased glomerular filtration rate (GFR), renal failure of unknown cause, presence of oxalate crystals in any biological fluid or tissue. Metabolic screening for urinary oxalate levels. Normal urinary oxalate excretion is less than 0.5 mmol/1.73 m2 per day or 45 mg/1.73 m2 per day. Levels greater than this are strongly supportive of the diagnosis of primary hyperoxaluria type 1. Diagnosis is confirmed by molecular genetic testing that demonstrates a variant of the AGXT gene. […] The initial medical management approaches, which are aimed to delay progressive renal decline, include use of pyridoxine, calcium oxalate crystallization inhibitors, hyperhydration, and dietary restrictions. Treatment with pyridoxine (vitamin B6) has been shown to decrease urine oxalate excretion in about 10 to 30% of patients, particularly those with homozygous p.Gly170Arg or p.Phe152lle variants.

• #7 Lumasiran for Primary Hyperoxaluria Type 1

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/lumasiran-for-primary-hyperoxaluria-type-1/

  Primary hyperoxaluria type 1 is a heterogeneous disorder with high variability in age and severity of symptoms at the time of presentation. Kidney stones are the most common manifestation that lead to the diagnosis of primary hyperoxaluria type 1. Patients can present from birth to adulthood with clinical presentation ranging from kidney stones to end stage renal disease (ESRD). […] Primary hyperoxaluria type 1 is considered a rare disease with an estimated prevalence of 1 to 3 patients per million people worldwide (mainly based on estimates from Europe). The incidence in Europe has been estimated at 1 in 120,000 live births per year. Estimating the prevalence and incidence is difficult owing to the wide variability in its clinical presentation and age of clinical onset. Patients often experience a considerable diagnostic delay; approximately 20 to 50% of patients have advanced chronic kidney disease, or even ESRD at the time of diagnosis.

• #7 Lumasiran for Primary Hyperoxaluria Type 1

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/lumasiran-for-primary-hyperoxaluria-type-1/

  As the disease progresses, individuals may require interventions for renal stone removal, dialysis, and renal/liver transplant. However, with conventional hemodialysis and peritoneal dialysis, the rate of oxalate removal is often less than the endogenous production of oxalate and plasma oxalate returns to 80% of the predialysis value within 24 hours and 95% within 48 hours after dialysis. As a consequence, despite standard maintenance dialysis therapy, plasma oxalate typically exceeds the supersaturation threshold of 30 micromol/L during a substantial amount of time between dialysis treatments, thereby increasing the risk and progression of systemic oxalosis. […] Liver transplantation is the only curative intervention as it corrects the underlying enzymatic defect due to mutations of the AGXT gene. In patients with significant chronic renal disease, renal transplant may also be required. Currently, multiple transplantation strategies are in use and include combined liver-renal transplantation, sequential liver and renal transplantation, isolated liver transplantation, and isolated renal transplantation. However, the optimal transplantation type or sequence remains uncertain.

• #7 Lumasiran for Primary Hyperoxaluria Type 1

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/lumasiran-for-primary-hyperoxaluria-type-1/

  The evidence for lumasiran for individuals with primary hyperoxaluria with preserved renal function consists of 1 phase 3 RCT (ILLUMINATE-A) in patients 6 years and older and 1 single arm prospective study (ILLUMINATE-B) in patients 6 years and younger. In both studies, patients with preserved renal function were enrolled (eGFR 30 mL/min/1.73 m2). In ILLUMINATE-A, the percent reduction in 24-hour urinary oxalate from baseline to month 6 was -65% and -12% in the lumasiran and placebo group, respectively, with a between-group mean difference of 53% (95% CI: 45 to 62%; p 0.0001). A similar effect was seen in patients with high baseline urinary oxalate values, and approximately half of patients receiving lumasiran achieved normal urinary oxalate values by month 6. […] The major limitation is the lack of data on clinical outcomes such as nephrolithiasis, nephrocalcinosis, and renal failure as both trials were not powered to assess these clinical endpoints. However, use of urinary oxalate as a surrogate for clinical outcomes in the pivotal trials may be justified based on the knowledge of the pathophysiology of the disease and the causal role of urinary oxalate in kidney stone formation, nephrocalcinosis, and loss of kidney function. Further, the consistency and size of treatment effect (more than half of patients receiving lumasiran achieved normal urinary oxalate levels at 6 months of treatment in ILLUMINATE-A) in clinical trials are indicative of the potential for a clinical benefit over the long term.

• #8

  https://www.omim.org/entry/260000

  A number sign (#) is used with this entry because of evidence that type II primary hyperoxaluria (HP2) is caused by homozygous or compound heterozygous mutation in the glyoxylate reductase/hydroxypyruvate reductase gene (GRHPR; 604296) on chromosome 9p13. […] The metabolic defect is deficiency of D-glycerate dehydrogenase/glyoxylate reductase leading to characteristic hyperoxaluria and excretion of L-glycerate, the cornerstone of diagnosis of this form of primary hyperoxaluria. […] Williams and Smith (1971) presented evidence that in HP2, hydroxypyruvate, present in excess because of deficiency in the enzyme that converts it to D-glycerate, stimulates oxidation of glycolate to oxalate, and decreases reduction of glyoxylate to glycolate. This is a novel explanation for the phenotypic consequences of a garrodian inborn error of metabolism.

• #8

  https://www.omim.org/entry/260000

  In patients with HP2, Seargeant et al. (1991) demonstrated combined deficiencies of D-glycerate dehydrogenase and glyoxylate reductase, which are attributable to a single enzyme. Deficiency of D-glycerate dehydrogenase activity presumably causes accumulation of its substrate, hydroxypyruvate, which is then converted to L-glycerate by the action of L-lactate dehydrogenase. Deficiency of glyoxylate reductase activity presumably causes impaired conversion of glyoxylate to glycolate. Conversion of glyoxylate to oxalate by L-lactate dehydrogenase would explain the observed hyperoxaluria. […] The transmission pattern of HP2 in the families reported by Takayama et al. (2014) was consistent with autosomal recessive inheritance. […] Cramer et al. (1999) found homozygosity for an identical mutation in the GRHPR gene (604296.0001) in 2 pairs of sibs from unrelated families with type II primary hyperoxaluria. […] Takayama et al. (2014) found the GRHPR c.103delG mutation (604296.0001) only in Caucasian patients of northern European or American origin, and the c.864delTG mutation (604296.0003) only in patients of Japanese or Chinese origin.

• #9 Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs

  https://www.mdpi.com/2218-273X/14/5/511

  PH2 is caused by a deficiency in the GRHPR enzyme, encoded by the GRHPR gene. […] Due to the deficiency of GRHPR, hydroxypyruvate and glyoxylate cannot be converted into D-glycerate and glycolate. […] PH3 stems from the functional loss of HOGA1, encoded by the HOGA1 gene, predominantly found in the liver and kidneys. […] The loss of HOGA1 function elevates the urine levels of 4-hydroxyglutamate (4OHGlu), 2,4-dihydroxyglutarate (DHG), HOG and oxalate. […] However, the exact mechanism causing this increase in oxalate levels remains unclear. […] The clinical phenotype and progression of PHs are contingent upon the severity and type of mutation, and its natural history is typically divided into two stages: initially, elevated oxalate synthesis is compensated for by hyperoxaluria, but, when the urinary oxalate reaches an extreme value of 1–2 mmol/1.73m²/day, it causes renal deposition and progressive kidney damage; the subsequent renal function decline impedes oxalate clearance, causing systemic oxalate accumulation and secondary organ damage.

• #9 Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs

  https://www.mdpi.com/2218-273X/14/5/511

  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. […] The deposition of calcium oxalate (CaOx) in the renal tubules and interstitium in PH can cause chronic tubulointerstitial inflammation and kidney stone obstruction, resulting in renal failure in over 70% of cases. […] PH1 results from a hepatic-specific deficiency in the AGT enzyme, encoded by the AGXT gene. […] Lacking AGT, glyoxylate in the peroxisomes fails to be converted into glycine; it is instead transported to the cytoplasm and converted into glycolate and oxalate through the actions of GRHPR and LDH.

• #9 Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs

  https://www.mdpi.com/2218-273X/14/5/511

  Systemic oxalosis, caused by elevated plasma oxalate (POx), leads to the extensive deposition of CaOx in various tissues, including the bone, retina, myocardium, vascular walls and skin. […] The diagnosis of PHs typically relies on a combination of clinical symptoms and laboratory data. […] The effective integration of genetic testing and clinical phenotype assessment enhances the application of precision medicine. […] The pathogenic gene AGXT, situated on 2q37.3, has been associated with 220 disease-causing mutations, disrupting AGT function via the loss of catalytic activity, mislocalization, accelerated degradation or protein aggregation. […] The predominant mutation in PH1 is p.G170R, associated with AGT mislocalization, which accounts for about 28–30% of mutated alleles, primarily found in Western populations.

• #9 Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs

  https://www.mdpi.com/2218-273X/14/5/511

  The relatively common mutations c.33dupC and p.I244T in PH1 exhibit varied frequencies among ethnicities. […] The current preclinical trials on direct enzyme replacement therapy (ERT) focus primarily on the restoration of AGT enzymes in the hepatic cells of PH1 hosts. […] Indirect ERT primarily involves liver cell transplantation (LCT) with normal function, either autologous or allogeneic. […] Oxalate induces various inflammatory pathways in the kidney, contributing to PH progression. […] Anakinra, an IL-1β receptor antagonist approved by the FDA to treat rheumatoid arthritis, also exerted a protective effect against inflammation and tissue damage during CaOx crystal-induced kidney injury in a mouse model.

• #10

  https://journals.lww.com/co-nephrolhypertens/fulltext/2024/07000/a_molecular_journey_on_the_pathogenesis_of_primary.7.aspx

  PH1 (OMIM259900), the most frequent and severe form, is caused by the deficit of alanine:glyoxylate aminotransferase (AGT), a Vitamin B6-dependent peroxisomal enzyme that catalyzes a transaminase reaction converting l-alanine and glyoxylate to pyruvate and glycine, respectively. […] In PH1 patients, peroxisomal glyoxylate generated from glycolate through glycolate oxidase (GO) is not detoxified by AGT, accumulates in the cytosol where it is oxidized to oxalate by LDH. […] The realization that PH1 is mostly a misfolding disease has paved the way for a re-evaluation of the therapy with Vitamin B6. […] An important aspect contributing to PH1 pathogenesis is that the AGXT gene comes in two allelic forms, i.e. a more frequent major allele and a polymorphic minor allele, characterized by a protein product (AGT-Mi) with p.Pro11Leu and p.Ile340Met substitutions.

• #10

  https://journals.lww.com/co-nephrolhypertens/fulltext/2024/07000/a_molecular_journey_on_the_pathogenesis_of_primary.7.aspx

  The relation between the molecular and clinical aspects of PH1 can be exploited not only to explain or predict treatment responsiveness, but also to interpret the effects of newly-identified mutations. […] PH2 is a very rare form of PH due to the deficit of GRHPR, a homodimeric enzyme that catalyzes the NADPH-dependent reduction of both glyoxylate and hydroxypyruvate generating glycolate and D-glycerate, respectively. […] ClinVar lists more than 100 mutations on the GRHPR gene as pathogenic or likely pathogenic, but the limited number of patients does not allow to define genotype/phenotype correlations. […] The genetic causes of PH3 are mutations in the HOGA1 gene encoding HOGA1, a mitochondrial enzyme involved in the last step of hydroxyproline catabolism. […] Nonetheless, the main enigma on the molecular pathogenesis of PH3 is how the deficit of an enzyme involved in glyoxylate synthesis could lead to increased oxalate production. […] Discoveries on the alterations in endogenous metabolism of glyoxylate and oxalate in PH have vigorously improved the understanding of disease mechanisms and the development of new drugs.

• #11 Secondary hyperoxaluria: Cause and consequence of chronic kidney disease | Nefrología

  https://www.revistanefrologia.com/en-secondary-hyperoxaluria-cause-consequence-chronic-articulo-S2013251424002359

  Secondary hyperoxaluria is a metabolic disorder characterized by an increase in urinary oxalate excretion. The etiology may arise from an increase in the intake of oxalate or its precursors, decreased elimination at the digestive level, or heightened renal excretion. Recently, the role of the SLC26A6 transporter in the etiopathogenesis of this disease has been identified. This transporter is active at both the intestinal and renal levels, and its mechanism of action is disrupted during systemic inflammation and metabolic syndrome, which could explain the rising incidence of secondary hyperoxaluria in recent decades. […] Hyperoxaluria is a metabolic disorder with increasing incidence in which there is an increased excretion of urinary oxalate. Excess oxalate may be due to inherited enzyme defects that lead to hepatic overproduction of oxalate (primary hyperoxaluria) or to increased intestinal absorption of oxalate (secondary hyperoxaluria). Oxalate is eliminated unmetabolized by the kidneys; thus, in hyperoxaluria the kidneys are the first organs affected, leading to nephrocalcinosis, lithiasis, and renal failure. It can also be deposited in all organs and tissues except the liver, a condition known as oxalosis.

• #11 Secondary hyperoxaluria: Cause and consequence of chronic kidney disease | Nefrología

  https://www.revistanefrologia.com/en-secondary-hyperoxaluria-cause-consequence-chronic-articulo-S2013251424002359

  The rising number of cases occurs alongside the group of entities encompassed by metabolic syndrome. The chronic inflammation produces an alteration in the SLC26A6 transporter which is present both at the intestinal and renal level, and this is key in the etiopathogenesis of this disease. […] The main organ affected in secondary hyperoxaluria is the kidney, which may suffer damage from nephrocalcinosis or renal lithiasis, potentially progressing to end-stage renal failure. However, calcium oxalate deposits can manifest in other organs, such as the retina, heart and peripheral nervous system, with a notable absence of deposits in the liver. […] The production of cytokines and several inflammatory molecules has been postulated as pathogenic agents of secondary hyperoxaluria, so immune modulation has been established as one of the possible lines of research. The inhibition of the nucleotide-binding, leucine-rich-repeat, pyrin domain containing 3 (NLRP3) inflammasome activation could reduce the cleavage of the proinflammatory cytokines interleukin 1 beta (IL-1) and interleukin 18 (IL-18) through caspase 1, as well as inhibit cell death induced by inflammation.

• #12 Hyperoxaluria and oxalosis // Middlesex Health

  https://middlesexhealth.org/learning-center/diseases-and-conditions/hyperoxaluria-and-oxalosis

  Some intestine problems cause the body to absorb more oxalate from foods. This can then increase the amount of oxalate in the urine. Crohn’s disease is one intestine problem that can lead to enteric hyperoxaluria. Another is short bowel syndrome, which can happen when parts of the small intestine are removed during surgery. […] If this happens, it might leave oxalate more available for the gut to absorb. Usually, oxalate combines with calcium in the gut and exits the body through stools. But when there is increased fat in the gut, calcium binds to the fat instead. This allows oxalate to be free in the gut and absorbed in the bloodstream. It’s then filtered by the kidneys. Roux-en-Y gastric bypass surgery also can lead to trouble absorbing fat in the gut, which raises the risk of hyperoxaluria.

• #12 Hyperoxaluria and oxalosis // Middlesex Health

  https://middlesexhealth.org/learning-center/diseases-and-conditions/hyperoxaluria-and-oxalosis

  Hyperoxaluria can be caused by a change in a gene, an intestine disease or eating too many foods that are high in oxalate. […] Oxalosis happens if you have primary or enteric hyperoxaluria and your kidneys stop working well enough. The body can no longer get rid of the extra oxalate, so the oxalate starts building up. First it builds up in the blood, then in the eyes, bones, skin, muscles, blood vessels, heart and other organs. […] Oxalosis can cause many health problems outside the kidneys in its late stages. These include: Bone disease. Anemia. Skin ulcers. Heart and eye problems. In children, serious problems developing and growing. […] With primary hyperoxaluria, the liver doesn’t make enough of a certain protein that prevents too much oxalate from being made. Or the protein doesn’t work as it should. The body gets rid of excess oxalate through the kidneys, in urine. The extra oxalate can combine with calcium to form kidney stones and crystals. These can damage the kidneys and cause them to stop working.

• #13 Hyperoxaluria/Oxalosis – Nephrology in 30 days

  https://ebrary.net/100321/health/hyperoxaluriaoxalosis

  Acquired or secondary forms of hyperoxaluria are commonly caused by excessive intake or absorption of oxalate or oxalate precursors. Poisoning with ethylene glycol, found most commonly in antifreeze, is a clinical example of a precursor that ultimately is metabolized to oxalate with tubulointerstitial calcium oxalate deposition. Similarly, anesthesia with methoxyflurane induced calcium oxalate deposition in kidney. Intravenous high-dose vitamin C (ascorbic acid), which is metabolized to oxalate, also induces renal deposition of calcium oxalate. Xylitol and E-ferol can cause tubulointerstitial disease from oxalate deposition. Short small bowel syndrome is a well-known gastrointestinal cause of secondary hyperoxaluria. Clinical disorders include small bowel resection or bypass, Crohn disease, celiac sprue, chronic pancreatitis, and Wilson disease. Treatment of obesity with either gastric bypass surgery or the weight loss drug orlistat has both been associated with fat malabsorption and enteric hyperoxaluria. Excessive absorption of oxalate occurs by the following mechanism. There is a high concentration of bile acids in the small intestine and colon. In the small intestine, bile acids saponify calcium, allowing unbound oxalate (which is usually complexed with calcium) to enter the large bowel. In the large bowel, bile acids increase the intestinal permeability to free oxalate entering from the small bowel. An additional mechanism may be reduced active secretion of oxalate into the bowel in the setting of reduced bowel surface area or bowel injury, which would increase plasma oxalate concentrations and subsequent hyperoxaluria. Certainly, volume contraction from associated malabsorption and diarrhea increases renal calcium oxalate crystal formation and deposition.

• #13 Hyperoxaluria/Oxalosis – Nephrology in 30 days

  https://ebrary.net/100321/health/hyperoxaluriaoxalosis

  Deposition of calcium oxalate crystals in the tubules and interstitium can lead to chronic tubulointerstitial nephritis and fibrosis. Hyperoxalosis can be divided into 2 clinical categories. One is the primary hyperoxalurias (types I and II) that are caused by hereditary disorders inherited recessively. Both of these disorders are characterized by tubular calcium oxalate deposition, which often extends into the renal interstitium and is associated with fibrosis and scarring. Type I develops from a deficiency of a-ketoglutarate:glyoxalate carboligase (cytosolic enzyme), leading to the excessive accumulation of oxalate, glyoxalate, and glycolate. Clinical manifestations of type 1 disease are the direct result of end-organ deposition (kidney predominantly) of calcium oxalate crystals. At a young age, patients develop hematuria, nephrolithiasis, renal colic, pyelonephritis, and CKD. ESRD and death often ensue by age 20 years. Type II, which is much less common, results from a deficiency of leukocyte D-glyceric dehydrogenase. Although formation of calcium oxalate stones is very common, CKD is unusual. Marked urinary excretion of oxalate occurs with both disorders associated with primary hyperoxaluria. As an example, urinary excretion often averages 240 mg/day compared with the normal total of 10 to 50 mg/day. Gross examination of these kidneys reveals dilated urinary systems, nephroliths, and infection while interstitial fibrosis and scarring are present histologically.

• #14 Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-022-00661-1

  Primary hyperoxaluria (PH) is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis and eventually kidney failure; the subsequent storage of oxalate can cause life-threatening systemic disease. […] In PH, the combination of intra-tubular and interstitial deposits of calcium oxalate, chronic tubulo-interstitial inflammation and kidney obstruction by stones leads to kidney failure in more than 70% of patients. […] As soon as glomerular filtration rate (GFR) falls below 30-40 ml/min/1.73 m², hepatic oxalate production exceeds renal removal, leading to systemic oxalate storage in various tissues, including bone, heart, vessels, nerves and eye, and causing life-threatening multi-organ disease. […] Importantly, the introduction of two new therapies based on RNA interference (RNAi) both of which substantially lower endogenous oxalate production in patients with PH1 have influenced the management of this disease.

• #15 Perspectives in primary hyperoxaluria — historical, current and future clinical interventions | Nature Reviews Urology

  https://www.nature.com/articles/s41585-021-00543-4

  Future work includes further clinical trials for promising therapeutics in the pipeline, identification of biomarkers of response to PH-directed therapy, optimization of drug development and delivery of new therapeutics. […] Hyperoxaluria requires TNF receptors to initiate crystal adhesion and kidney stone disease. […] NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. […] The macrophage phenotype and inflammasome component NLRP3 contributes to nephrocalcinosis-related chronic kidney disease independent from IL-1-mediated tissue injury. […] Oxalate, inflammasome, and progression of kidney disease.

• #15 Perspectives in primary hyperoxaluria — historical, current and future clinical interventions | Nature Reviews Urology

  https://www.nature.com/articles/s41585-021-00543-4

  Primary hyperoxalurias are a devastating family of diseases leading to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease. […] 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. […] New therapeutics being developed for PHs take advantage of biochemical knowledge about oxalate synthesis and metabolism to specifically target these pathways, with the goal of decreasing the accumulation and deposition of plasma oxalate in the body. […] Lumasiran, a mRNA therapeutic targeting glycolate oxidase, was the first primary hyperoxaluria-specific therapeutic approved by the European Medicines Agency and the FDA in 2020.

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