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Hyperoxaluria
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| Hyperoxaluria | |
|---|---|
| Other names | Bird's disease |
 | |
| Oxalate | |
| Specialty | Endocrinology  |
Hyperoxaluria is an excessive urinary excretion of oxalate. Individuals with hyperoxaluria often have calcium oxalate kidney stones. It is sometimes called Bird's disease, after Golding Bird, who first described the condition.
Presentation
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Causes
[edit]Hyperoxaluria can be primary (as a result of a genetic defect) or secondary to another disease process.[citation needed]
Type I primary hyperoxaluria (PH1) is associated mutations in the gene AGXT encoding Serine Pyruvate Aminotransferase, a key enzyme involved in oxalate metabolism. PH1 is an example of a protein mistargeting disease, wherein AGXT shows a trafficking defect. Instead of being trafficked to peroxisomes, it is targeted to mitochondria, where it is metabolically deficient despite being catalytically active. Type II is associated with Glyoxylate Reductase/Hydroxypyruvate Reductase (GRHPR).[1]
Secondary hyperoxaluria can occur as a complication of jejunoileal bypass, or in a patient who has lost much of the ileum with an intact colon. In these cases, hyperoxaluria is caused by excessive gastrointestinal oxalate absorption.[2]
Excessive intake of oxalate-containing food, such as rhubarb, may also be a cause in rare cases.[3]
Diagnosis
[edit]Types
[edit]The types are the following:[citation needed]
- Primary hyperoxaluria
- Enteric hyperoxaluria
- Idiopathic hyperoxaluria
- Oxalate poisoning
Treatment
[edit]The main therapeutic approach to primary hyperoxaluria is still restricted to symptomatic treatment, i.e. kidney transplantation once the disease has already reached mature or terminal stages. However, through genomics and proteomics approaches, efforts are currently being made to elucidate the kinetics of AGXT folding which has a direct bearing on its targeting to appropriate subcellular localization. A child with primary hyperoxaluria was treated with a liver and kidney transplant.[4] A favorable outcome is more likely if a kidney transplant is complemented by a liver transplant, given the disease originates in the liver.[citation needed]
Secondary hyperoxaluria is much more common than primary hyperoxaluria, and should be treated by limiting dietary oxalate and providing calcium supplementation.[citation needed]
Lactate deydrogenase A (LDHA) inhibitors (such as CHK-336) have been evaluated in clinical trials for treatment of primary hyperoxaluria, though none have been approved as of 2025.[5]
References
[edit]- ^ "Primary hyperoxaluria - Genetics Home Reference". Archived from the original on April 8, 2005.
- ^ Surgery PreTest Self-Assessment and Review, Twelfth Edition
- ^ Marc Albersmeyer; Robert Hilge; Angelika Schröttle; Max Weiss; Thomas Sitter; Volker Vielhauer (30 October 2012). "Acute kidney injury after ingestion of rhubarb: secondary oxalate nephropathy in a patient with type 1 diabetes". BMC Nephrology. 13: 141. doi:10.1186/1471-2369-13-141. ISSN 1471-2369. PMC 3504561. PMID 23110375. Wikidata Q34461274.
- ^ "India News & Business - MSN India: News, Business, Finance, Sports, Politics & more. - News". Archived from the original on 2007-09-29. Retrieved 2007-05-09.
- ^ Cox, Jennifer H.; Boily, Marc-Olivier; Caron, Alexandre; Sheng, Tao; Wu, Joyce; Ding, Jinyue; Gaudreault, Samuel; Chong, Oliver; Surendradoss, Jayakumar; Gomez, Robert; Lester, Jeffrey; Dumais, Valerie; Li, Xingsheng; Gumpena, Rajesh; Hall, Matthew D. (2025-04-07). "Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment". Journal of the American Society of Nephrology. 36 (8): 1535–1547. doi:10.1681/ASN.0000000690. ISSN 1046-6673. PMC 12342074. PMID 40193200.
External links
[edit]Hyperoxaluria
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Overview
Definition
Hyperoxaluria is a metabolic disorder characterized by excessive urinary excretion of oxalate, the end product of endogenous oxalate metabolism and dietary absorption. In adults, it is typically defined as urinary oxalate excretion exceeding 40 mg (0.45 mmol) per 24 hours, while in children, the threshold is greater than 0.5 mmol per 1.73 m² body surface area per 24 hours. Normal urinary oxalate excretion in healthy adults ranges from 20 to 40 mg per 24 hours, reflecting the balance between hepatic production, intestinal absorption, and renal clearance. A key distinction exists between hyperoxaluria and oxalosis: while hyperoxaluria refers specifically to elevated oxalate levels in the urine, oxalosis denotes the systemic deposition of calcium oxalate crystals in various tissues, such as the kidneys, heart, bones, and skin, which arises as a complication when renal function declines and plasma oxalate accumulates. Normal plasma oxalate concentrations are typically below 2 µmol/L in individuals with preserved kidney function, serving as a marker to differentiate localized urinary excess from widespread tissue involvement. The condition was first described in the 1920s, with early reports of recurrent calcium oxalate nephrolithiasis linked to idiopathic hyperoxaluria, and the genetic basis of primary forms was elucidated in the late 1980s and 1990s through identification of mutations in key enzymes involved in glyoxylate metabolism.Epidemiology
Hyperoxaluria encompasses both primary and secondary forms, with primary hyperoxaluria (PH) being a rare genetic disorder. Clinical prevalence is estimated at 1-3 individuals per million population worldwide, though recent genetic analyses (as of 2025) suggest a higher overall prevalence of approximately 1 in 59,000 (about 17 per million) due to underdiagnosis, with type-specific estimates of PH1 at 1 in 209,000 (~5 per million), PH2 at 1 in 863,000 (~1 per million), and PH3 at 1 in 91,000 (~11 per million).[5] The estimated incidence of PH is approximately 1-3 per 100,000 live births, with PH1 accounting for about 1 per 120,000 live births and comprising 70-80% of cases; no significant differences are observed across sexes.[6] PH1 exhibits notable geographic variations, with higher prevalence in regions with high rates of consanguineous marriages, such as parts of North Africa (e.g., Libya) and the Middle East (e.g., Turkey), where consanguinity in affected families can exceed 50%.[7][8] PH typically manifests in childhood, with an infantile form presenting before 1 year of age and a juvenile form between 1 and 18 years; the median age at onset is around 5 years, and distribution is equal between males and females.[9] Secondary hyperoxaluria, in contrast, is more common than the primary form, particularly in populations with predisposing conditions like inflammatory bowel disease (IBD) or post-bariatric surgery.[10] Its incidence has risen since the 2000s, correlating with increased bariatric procedures for obesity management, where hyperoxaluria prevalence can exceed 30% in affected patients due to enteric oxalate absorption.[11] This form predominates in Western countries with higher rates of obesity and surgical interventions.[12]Pathophysiology
Oxalate Metabolism
Oxalate is an end product of several metabolic pathways in the human body, with endogenous synthesis occurring primarily in the liver through the glyoxylate detoxification pathway localized in peroxisomes. This pathway processes glyoxylate, a toxic intermediate derived from precursors such as glycolate, hydroxyproline, and glycine, to prevent its conversion into oxalate via lactate dehydrogenase. Key enzymes in this process include alanine-glyoxylate aminotransferase (AGXT), which catalyzes the transamination of glyoxylate to glycine within peroxisomes, thereby detoxifying it and averting oxalate accumulation. Other critical enzymes are glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which operates in the cytosol and mitochondria to reduce glyoxylate to glycolate, and 4-hydroxy-2-oxoglutarate aldolase (HOGA1), involved in the mitochondrial breakdown of hydroxyproline-derived intermediates that feed into glyoxylate production. Endogenous oxalate synthesis typically contributes about 50% of the total urinary oxalate in healthy individuals. Dietary oxalate represents the other major source, accounting for 20-50% of urinary oxalate excretion, with the exact proportion varying based on intake and absorption efficiency. High-oxalate foods such as spinach, rhubarb, beets, nuts, and chocolate are prominent contributors, as they contain soluble oxalate that can be readily absorbed. Intestinal absorption of dietary oxalate primarily occurs in the small intestine and colon, with an average absorption rate of 10-15% in healthy adults on a standard diet; this process is significantly modulated by dietary calcium, which binds oxalate in the gut lumen to form insoluble calcium oxalate complexes that are largely excreted in feces, thereby reducing bioavailability. Factors like low calcium intake or gut dysbiosis can increase absorption, potentially elevating systemic oxalate levels. The kidneys play a central role in oxalate excretion, filtering nearly all plasma oxalate at the glomerulus due to its low molecular weight and lack of protein binding. Of the filtered load, a substantial portion is reabsorbed in the proximal tubule via passive paracellular diffusion and active transport mechanisms, but the net result is that virtually all absorbed and endogenously produced oxalate is eliminated via urine to maintain homeostasis. Normal 24-hour urinary oxalate excretion in healthy adults ranges from 10 to 40 mg, reflecting the balance between synthesis, absorption, and renal clearance. Disruptions in the glyoxylate pathway can lead to excessive endogenous oxalate production, contributing to hyperoxaluria. Oxalate's tendency to bind calcium in urine can promote the formation of calcium oxalate crystals, a key step in stone precipitation under supersaturated conditions.Disease Mechanisms
In primary hyperoxaluria, inherited enzyme deficiencies disrupt glyoxylate metabolism in the liver, leading to accumulation of glyoxylate and its subsequent conversion to oxalate, resulting in hepatic overproduction of oxalate that exceeds the kidneys' excretory capacity.[13] Specific defects include alanine-glyoxylate aminotransferase (AGXT) in type 1, glyoxylate reductase/hydroxypyruvate reductase (GRHPR) in type 2, and 4-hydroxy-2-oxoglutarate aldolase (HOGA1) in type 3, each causing elevated oxalate synthesis from glyoxylate precursors.[1] This overproduction drives urinary oxalate levels above 40-45 mg/day, promoting hyperoxaluria and subsequent renal pathology.[13] In secondary hyperoxaluria, particularly the enteric form, fat malabsorption from conditions such as Crohn's disease or bariatric surgery reduces intraluminal calcium availability in the colon, allowing unbound dietary oxalate to be hyperabsorbed via paracellular and transcellular pathways.[13] This increased colonic uptake elevates systemic oxalate load without endogenous overproduction, often raising urinary oxalate to levels comparable to primary forms.[1] Elevated urinary oxalate concentrations lead to supersaturation of calcium oxalate, where the product of calcium and oxalate concentrations exceeds the solubility product, favoring the formation of calcium oxalate monohydrate crystals that deposit primarily in renal tubules.[13] These crystals initiate nephrolithiasis and nephrocalcinosis by adhering to tubular epithelium, with the supersaturation of calcium oxalate being 10 times more dependent on rises in urinary oxalate than on equimolar rises in urinary calcium.[13] As glomerular filtration rate declines below 30-40 mL/min/1.73 m², plasma oxalate accumulates due to impaired renal clearance, enabling systemic dissemination and deposition of calcium oxalate crystals in extrarenal tissues such as the heart, bones, and blood vessels, a condition known as oxalosis.[14] This progression is more common in primary hyperoxaluria but can occur in severe secondary cases with advanced kidney dysfunction.[13] Crystal deposition triggers crystal-induced nephropathy through direct tubular obstruction, which impairs urine flow and causes epithelial cell injury, compounded by oxidative stress from reactive oxygen species generated via NADPH oxidase and mitochondrial dysfunction.[15] Additionally, crystals activate the NLRP3 inflammasome in renal cells and macrophages, releasing proinflammatory cytokines like IL-1β and promoting pyroptosis, fibrosis, and chronic inflammation that accelerate progression to end-stage renal disease.[15]Classification
Primary Hyperoxaluria
Primary hyperoxaluria (PH) encompasses a group of rare autosomal recessive disorders characterized by hepatic overproduction of oxalate due to defects in glyoxylate metabolism, leading to excessive urinary oxalate excretion and recurrent nephrolithiasis.[16] The condition is classified into three main genetic subtypes—PH1, PH2, and PH3—each resulting from biallelic pathogenic variants in distinct genes encoding key enzymes in the peroxisomal or mitochondrial glyoxylate detoxification pathway.[17] Inheritance follows an autosomal recessive pattern, with estimated carrier frequencies varying by subtype and population: approximately 1:195 for PH1, 1:279 for PH2, and 1:185 for PH3 based on exome sequencing data from diverse cohorts.[18] These frequencies suggest underdiagnosis, particularly in non-European populations, and highlight the need for genetic screening in families with recurrent kidney stones.[19] PH type 1 (PH1), the most prevalent and severe subtype accounting for 70-80% of cases, arises from pathogenic variants in the AGXT gene located on chromosome 2q37.3, which encodes the peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT).[16] Over 150 mutations have been identified, with common missense variants including p.Gly170Arg (G170R), p.Phe152Ile, and p.Ile244Thr; the G170R mutation is particularly associated with pyridoxine (vitamin B6) responsiveness in 10-50% of PH1 patients, as it enhances residual AGT activity under high cofactor conditions.[16] Clinically, PH1 often presents with infantile nephrocalcinosis and rapid progression to end-stage kidney disease (ESKD) in 10-50% of cases by adolescence, though adult-onset milder forms occur.[17] Biochemically, it features markedly elevated urinary oxalate (>0.5 mmol/1.73 m²/24 h) and glycolate excretion, with plasma oxalate levels exceeding 30 µmol/L indicating systemic oxalosis risk.[16] PH type 2 (PH2), representing 5-10% of cases, results from biallelic variants in the GRHPR gene on chromosome 9p13.2, encoding the cytosolic and mitochondrial enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR).[20] More than 20 mutations are reported, including the founder variant c.103delG (p.Asp35Thrfs*11) prevalent in European and African American populations, leading to absent enzyme activity.[20] This subtype is generally milder than PH1, with recurrent urolithiasis starting in childhood but progression to ESKD in only about 20-30% of patients by adulthood, and rare systemic involvement.[17] Distinctive biochemical markers include elevated urinary L-glycerate (>0.1 mmol/1.73 m²/24 h) alongside hyperoxaluria, aiding differentiation from other PH types, though glycolate levels remain normal.[20] PH type 3 (PH3), comprising 10-20% of cases and often underrecognized, stems from pathogenic variants in the HOGA1 gene on chromosome 10q24.2, which encodes the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA1) involved in hydroxyproline metabolism.[21] Common mutations include c.700+5G>T (splice site) and c.944_946del (p.Glu315del), with over 30 variants described, many resulting in enzyme instability or reduced activity.[21] Presentation typically involves calcium oxalate nephrolithiasis in early childhood (median age 1.9 years), but the course is heterogeneous: hyperoxaluria resolves spontaneously in up to 50% by adolescence, while 10-20% progress to chronic kidney disease, and fewer than 5% reach ESKD by age 40, without reported systemic oxalosis.[22] Biochemically, it is marked by elevated urinary oxalate (0.5-1.0 mmol/1.73 m²/24 h) and diagnostic metabolites 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG), with milder plasma oxalate elevations during progression.[21] Rare variants beyond these three subtypes have been proposed, such as potential PH type IV linked to SCN9A mutations affecting oxalate transport, but this classification remains debated and unestablished in major consensus guidelines as of 2023.[23]Secondary Hyperoxaluria
Secondary hyperoxaluria refers to elevated urinary oxalate levels resulting from non-genetic factors that increase oxalate absorption, production, or intake, distinguishing it from inherited metabolic defects.[13] This condition arises primarily from acquired disruptions in oxalate homeostasis, such as enhanced intestinal absorption or excessive exogenous oxalate load, leading to hyperoxaluria typically exceeding 40 mg/day (0.45 mmol/day) in adults.[24] Enteric hyperoxaluria, a major subtype, occurs in malabsorptive gastrointestinal disorders where fat malabsorption plays a central role. In conditions like Crohn's disease, short bowel syndrome, or post-bariatric surgery (e.g., Roux-en-Y gastric bypass), unabsorbed fatty acids bind dietary calcium in the gut, reducing calcium availability to form insoluble calcium oxalate complexes and thereby increasing the pool of soluble oxalate available for colonic absorption.[25] This heightened absorption can elevate urinary oxalate to levels as high as 100-200 mg/day, contributing to nephrolithiasis or oxalate nephropathy.[26] The prevalence of enteric hyperoxaluria has risen with the increased incidence of bariatric procedures, affecting 20-70% of patients post-surgery, particularly after malabsorptive procedures.[26] Dietary hyperoxaluria stems from excessive consumption of oxalate-rich foods, which can overwhelm normal intestinal degradation and absorption mechanisms. Common sources include nuts, tea, spinach, rhubarb, and chocolate, where intakes exceeding 250 mg/day—far above the typical dietary range of 50-200 mg/day—promote hyperoxaluria, particularly in individuals with idiopathic high oxalate absorption efficiency. For instance, regular consumption of black tea or almond-based products has been linked to urinary oxalate elevations of 50-100 mg/day in susceptible absorbers. Intestinal oxalate absorption, normally limited to 10-15% of dietary load due to bacterial degradation and calcium binding, can increase under high dietary exposure.[27]Dietary Oxalate Intake and Secondary Hyperoxaluria
Typical daily dietary oxalate intake in a standard varied or Western diet ranges from 80–300 mg, with averages commonly cited around 150–200 mg. Dietary oxalate normally contributes 10–20% to urinary oxalate in healthy individuals (with absorption rates of 2–15%), but this can rise significantly in those with malabsorption or high consumption. High oxalate intake generally refers to sustained consumption exceeding 200–250 mg/day, which can elevate urinary oxalate and contribute to secondary hyperoxaluria, particularly when combined with low calcium intake, dehydration, or gastrointestinal conditions. For kidney stone prevention or hyperoxaluria management, guidelines recommend limiting dietary oxalate to under 100 mg/day, and sometimes as low as 40–50 mg/day in high-risk cases.High-Oxalate Foods (Approximate Content)
Oxalate levels vary by preparation and source, but key high-oxalate foods include:- Spinach: ~656 mg per 1 cup raw (~30 g); ~755 mg per ½ cup cooked.
- Rhubarb: ~541 mg per ½ cup stewed or raw.
- Swiss chard or beet greens: 300–800+ mg per ½–1 cup cooked.
- Beets: ~76–152 mg per ½–1 cup.
- Almonds: ~122 mg per 1 oz (~22 kernels).
- Soy products: Firm tofu ~235 mg per 3 oz; soy milk ~336 mg per cup.
- Potatoes: ~97 mg per medium baked with skin.
- Other: Buckwheat groats ~133 mg per ½ cup cooked; navy beans ~76 mg per ½ cup; okra ~57 mg per ½ cup; cocoa/dark chocolate and brewed black tea (variable but additive).
Examples of High Oxalate Intake
- A large green smoothie: 1–2 cups raw spinach (~650–1,300 mg) + almond milk or nuts (~300+ mg) can exceed 1,000 mg in one serving.
- Plant-heavy day: Breakfast with almond butter/oatmeal; lunch spinach salad/stir-fry with chard; dinner tofu/buckwheat; snacks chocolate/tea — easily 300–600+ mg.
- Single high-load meal: Baked potato with skin (~97 mg) + cooked spinach side (~755 mg) + almonds (~122 mg) + tea/chocolate — hundreds of mg.