Re: 옥살산 대사와 항상성 신장 질환에서 특히 주의해야!! 2023년 nature

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Nat Rev Nephrol

. Author manuscript; available in PMC: 2023 Jun 19.

Published in final edited form as: Nat Rev Nephrol. 2022 Nov 3;19(2):123–138. doi: 10.1038/s41581-022-00643-3

Oxalate homeostasis

Theresa Ermer 1, Lama Nazzal 2, Maria Clarissa Tio 3, Sushrut Waikar 4, Peter S Aronson 5, Felix Knauf 5,6,✉

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PMCID: PMC10278040  NIHMSID: NIHMS1904631  PMID: 36329260

The publisher's version of this article is available at Nat Rev Nephrol

Abstract

Oxalate homeostasis is maintained through a delicate balance between endogenous sources, exogenous supply and excretion from the body. Novel studies have shed light on the essential roles of metabolic pathways, the microbiome, epithelial oxalate transporters, and adequate oxalate excretion to maintain oxalate homeostasis. In patients with primary or secondary hyperoxaluria, nephrolithiasis, acute or chronic oxalate nephropathy, or chronic kidney disease irrespective of aetiology, one or more of these elements are disrupted. The consequent impairment in oxalate homeostasis can trigger localized and systemic inflammation, progressive kidney disease and cardiovascular complications, including sudden cardiac death. Although kidney replacement therapy is the standard method for controlling elevated plasma oxalate concentrations in patients with kidney failure requiring dialysis, more research is needed to define effective elimination strategies at earlier stages of kidney disease. Beyond well-known interventions (such as dietary modifications), novel therapeutics (such as small interfering RNA gene silencers, recombinant oxalate-degrading enzymes and oxalate-degrading bacterial strains) hold promise to improve the outlook of patients with oxalate-related diseases. In addition, experimental evidence suggests that anti-inflammatory medications might represent another approach to mitigating or resolving oxalate-induced conditions.

초록

옥살산 항상성은

내인성 원천, 외인성 공급, 및 신체에서의 배설 사이의

섬세한 균형을 통해 유지됩니다.

새로운 연구들은

옥살산 균형을 유지하는 데 있어

대사 경로, 미생물군집, 상피 옥살산 운반체, 및 적절한 옥살산 배설의 필수적인 역할을 밝혀냈습니다.

원발성 또는 이차성 고옥살산혈증, 신결석증, 급성 또는 만성 옥살산 신장병,

또는 원인에 관계없이 만성 신장 질환을 가진 환자에서는

이러한 요소 중 하나 이상이 손상됩니다.

이에 따른 옥살산 균형 장애는

국소적 및 전신성 염증, 진행성 신장 질환, 심혈관 합병증(급성 심장 사망 포함)을 유발할 수 있습니다.

신장 기능 장애로 투석이 필요한 환자의

혈장 옥살산 농도를 조절하기 위해

신장 대체 요법이 표준 치료법이지만,

신장 질환의 초기 단계에서 효과적인 배설 전략을 정의하기 위해 추가 연구가 필요합니다.

기존에 알려진 치료법(예: 식이 조절)을 넘어,

소형 간섭 RNA 유전자 억제제,

재조합 옥살산 분해 효소,

옥살산 분해 세균 균주와 같은 새로운 치료법이

옥살산 관련 질환 환자의 예후를 개선할 가능성을 보여주고 있습니다.

또한 실험적 증거는

항염증 약물이 옥살산 유발 질환을 완화하거나 해결하는

또 다른 접근법이 될 수 있음을 시사합니다.

Introduction

Oxalate, a seemingly inconspicuous dicarboxylic acid, is one of the 20 uraemic toxins with the highest relative increase in uraemia1. Oxalate homeostasis is maintained by a complex interplay of supply, metabolic pathways and excretion (Fig. 1). Consequently, oxalate homeostasis can be disturbed by numerous factors. Genetic mutations can disrupt endogenous oxalate biosynthesis and transport, whereas dietary and microbial factors as well as gastrointestinal pathologies can affect oxalate absorption. Kidney disease can also impair the elimination of oxalate, thereby turning a harmless, low-concentration metabolite into a serious multisystemic threat that can affect nearly every organ and tissue in the body, including the cardiovascular system2–4.

소개

옥살산은 눈에 띄지 않는 이산화탄소산으로,

요독증에서 상대적 증가율이 가장 높은 20가지 요독 독소 중 하나입니다.1

옥살산 균형은

공급, 대사 경로, 배설의 복잡한 상호작용을 통해 유지됩니다(그림 1).

따라서

옥살산 균형은 다양한 요인에 의해 방해받을 수 있습니다.

유전적 변이는

내인성 옥살산 생합성 및 운반을 방해할 수 있으며,

식이 요인, 미생물 요인 및 위장관 질환은 옥살산 흡수를 영향을 미칠 수 있습니다.

신장 질환은 옥살산 배설을 방해하여

무해한 저농도 대사물을 심장혈관계를 포함한

신체 거의 모든 장기 및 조직에 영향을 미치는 심각한 다기관 질환으로 전환시킬 수 있습니다2–4.

Fig. 1 |. Oxalate homeostasis.

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a, Physiological oxalate homeostasis. Oxalate homeostasis is maintained by a delicate interplay of supply (that is, hepatic production, gastrointestinal (GI) absorption of dietary oxalate and tubular reabsorption of circulating oxalate) and excretion (GI secretion and faecal oxalate, glomerular filtration, tubular secretion and urinary oxalate). Physiological plasma oxalate concentrations of 1–5 μM have no known negative effects on the cardiovascular system. b, Disturbed oxalate homeostasis and the consequences of hyperoxalaemia. Oxalate homeostasis might be disturbed by alterations in numerous pathways. Plasma oxalate concentrations can increase owing to decreased urinary excretion in chronic kidney disease, increased hepatic production in primary hyperoxaluria or increased GI absorption in enteric hyperoxaluria. When kidney function is still sufficiently high to enable compensatory oxalate excretion in the kidney, hyperoxaluria can result in nephrocalcinosis, tubular toxicity and obstruction. Loss of kidney excretory function can lead to supersaturation of plasma with oxalate, which can have severe adverse effects on the cardiovascular system. High plasma oxalate is associated with sudden cardiac death, coronary artery disease, congestive heart failure and vascular calcification. Oxalate can also deposit in other tissues such as bone, thyroid, spleen and lungs.

a, 생리적 옥살산 균형. 옥살산 균형은 공급(즉, 간에서 생성되는 옥살산, 식이 옥살산의 위장관(GI) 흡수 및 순환 중인 옥살산의 관상 재흡수)과 배설(GI 분비 및 대변 옥살산, 사구체 여과, 관상 분비 및 요중 옥살산) 사이의 섬세한 상호작용에 의해 유지됩니다. 생리적 혈장 옥살산 농도 1–5 μM은 심혈관 시스템에 알려진 부정적 영향이 없습니다.

b, 옥살산 균형 장애와 고옥살산혈증의 결과. 옥살산 균형은 다양한 경로의 변화로 인해 방해받을 수 있습니다. 만성 신장 질환으로 인한 요로 배설 감소, 원발성 고옥살산혈증에서의 간 생성 증가, 장성 고옥살산혈증에서의 위장관 흡수 증가로 인해 혈장 옥살산 농도가 증가할 수 있습니다. 신장 기능이 여전히 충분하여 신장에서 보상성 옥살산 배설이 가능할 경우, 고옥살산혈증은 신장 석회화, 관상 독성 및 폐쇄를 초래할 수 있습니다. 신장 배설 기능의 상실은 혈장 옥살산 과포화를 초래할 수 있으며, 이는 심혈관 시스템에 심각한 부작용을 일으킬 수 있습니다. 높은 혈장 옥살산 농도는 급성 심장 사망, 관상동맥 질환, 심부전 및 혈관 석회화와 연관되어 있습니다. 옥살산은 뼈, 갑상선, 비장 및 폐와 같은 다른 조직에도 침착될 수 있습니다.

Increased serum or urine oxalate concentrations have been associated with progressive kidney disease5,6, cardiovascular conditions2,3, and cellular and systemic inflammation7–9. A 2021 study also identified elevated serum oxalate concentrations as a novel risk factor for sudden cardiac death in patients receiving dialysis3. Novel translational research findings, for example, regarding the pathogenesis of atherosclerosis10, are currently helping to move the field from mere association to causation. Further discoveries about the pathophysiology of uraemic toxins such as oxalate might help reduce the still unacceptably high excess mortality of patients with kidney and cardiovascular disease. As new evidence on the clinical implications of excess oxalate accumulates, it is crucial to understand the basic principles governing oxalate homeostasis. New studies have, for example, further defined the crucial involvement of epithelial transport proteins and the gut microbiome in oxalate regulation11,12.

In this Review, we will examine the pathways of oxalate in the body, highlighting core mechanistic steps and their clinical implications. This information will provide the groundwork for a discussion of the pathophysiological consequences of oxalate accumulation. We will also consider novel interventional, pharmacological and microbial approaches to prevent, mitigate or resolve oxalate-related conditions that affect the kidney, heart and other organs.

혈청 또는 소변 옥살산 농도 증가가

진행성 신장 질환5,6, 심혈관 질환2,3,

세포 및 전신 염증7–9과 연관되어 있습니다.

2021년 연구에서는 투석 중인 환자에서

급성 심장 사망의 새로운 위험 요인으로

혈청 옥살산 농도 증가를 확인했습니다3.

동맥경화증의 병리 메커니즘에 대한 새로운 번역 연구 결과10 등은

현재 이 분야를 단순한 연관성에서

인과 관계로 발전시키는 데 기여하고 있습니다.

요산 독소인 옥살산의 병리생리학에 대한 추가적인 발견은

신장 및 심혈관 질환 환자의 여전히 용납할 수 없는

높은 초과 사망률을 줄이는 데 도움이 될 수 있습니다.

과도한 옥살산 축적의 임상적 함의에 대한 새로운 증거가 축적됨에 따라,

옥살산 균형 조절을 지배하는 기본 원리를 이해하는 것이 중요합니다.

새로운 연구는 예를 들어,

상피 운반 단백질과 장 미생물군집이 옥살산 조절에 핵심적으로 관여한다는 점을

더욱 명확히 했습니다11,12.

이 리뷰에서는

체내 옥살산의 경로를 살펴보고

핵심 메커니즘 단계와 임상적 의미를 강조할 것입니다.

이 정보는

옥살산 축적의 병리생리학적 결과에 대한 논의의 기반을 제공할 것입니다.

또한

신장, 심장 및 기타 장기에 영향을 미치는 옥살산 관련 질환을

예방, 완화 또는 해결하기 위한 새로운 개입, 약물 및 미생물학적 접근법을 고려할 것입니다.

Oxalate sources and metabolism

Oxalate is the ionized conjugate base of oxalic acid, which is the simplest dicarboxylic acid13,14. Oxalate is either produced endogenously as a metabolic end-product or can be ingested as a component of numerous foods, drinks or chemicals (Fig. 1a). Healthy individuals typically maintain a plasma oxalate concentration of 1–5 μM. Of note, the ‘normal’ plasma oxalate range can vary depending on the measurement method; for example, one study reported that concentrations up to 11 μM were normal15–17.

Hepatic oxalate biosynthesis has been estimated to contribute 50–80% of total body oxalate levels, based on the measurement of the relative contribution of varying dietary oxalate intake on urinary oxalate levels18. Numerous molecules derived from amino acid and carbohydrate metabolism have been identified or suggested to be oxalate precursors (Fig. 2 and Table 1). For example, hydroxyproline, which derives from collagen catabolism, contributes an estimated 15% to urinary oxalate in healthy individuals19. Glycolate is another well-established oxalate precursor and has been estimated to contribute to <3% of oxalogenesis via peroxisomal metabolism20. An ongoing non-randomized clinical trial will use 13C2-glycolate infusion to estimate the contribution of glycolate to oxalate formation in healthy individuals21. Of note, although glycolate is thought to be present in most cells, its biological role is incompletely characterized22. Glyoxal is a product of carbohydrate autoxidation, lipid peroxidation and protein glycation that is primarily detoxified to glycolate by the glyoxalase system23,24. Oxalate synthesis from glyoxal in human erythrocytes and hepatocytes has been reported in vitro24,25, although a subsequent study suggested that this pathway might be of minor relevance in vivo26. Glyoxal was also proposed as the missing link between nephrolithiasis, hyperoxaluria and diabetes given that both glyoxal and oxalate excretion are elevated in patients with diabetes23,27. Finally, glycine is a small amino acid estimated to contribute <5% to urinary oxalate under physiological conditions28 (Fig. 2). Other amino acids, such as tryptophan, tyrosine and phenylalanine, are also potential oxalate precursors but are estimated to make only minor contributions to endogenous oxalate28.

옥살산의 원천과 대사

옥살산염은

옥살산의 이온화된 공액 기저체로,

가장 간단한 다이카르복실산입니다13,14.

simplest dicarboxylic acid

옥살산염은

대사 최종 산물로 내생적으로 생성되거나,

다양한 식품, 음료 또는 화학물질의 구성 성분으로 섭취될 수 있습니다(그림 1a).

건강한 개인은

일반적으로 혈장 옥살산염 농도를

1–5 μM로 유지합니다.

참고로, ‘정상’ 혈장 옥살산염 범위는 측정 방법에 따라 달라질 수 있습니다.

예를 들어, 한 연구에서는 11 μM까지의 농도가 정상으로 보고되었습니다15–17.

간에서 생성되는 옥살산염은

식이 옥살산염 섭취량의 상대적 기여도를

소변 옥살산염 농도로 측정했을 때

전체 체내 옥살산염 수준의 50–80%를 차지하는 것으로 추정되었습니다18.

아미노산 및 탄수화물 대사에서 유래한 수많은 분자들이

옥살산 전구체로 확인되거나 제안되었습니다(그림 2 및 표 1).

예를 들어,

콜라겐 분해에서 유래한 히드록시프로린은

건강한 개인의 요중 옥살산에 약 15%를 기여하는 것으로 추정되었습니다19.

글리콜레이트는 또 다른 잘 알려진 옥살산 전구체로,

과산화체 대사20를 통해 옥살산 생성에 3% 미만을 기여하는 것으로 추정됩니다.

진행 중인 비무작위 임상 시험에서는

건강한 개인의 옥살산 형성에 대한 글리콜레이트의 기여도를 추정하기 위해

13C2-글리콜레이트 정맥 주입을 사용할 예정입니다21.

주목할 점은

글리콜레이트가 대부분의 세포에 존재한다고 생각되지만,

그 생물학적 역할은 완전히 규명되지 않았다는 점입니다22.

글리옥살은

탄수화물 자동산화, 지질 과산화 및 단백질 당화 반응의 산물로,

주로 글리옥살라제 시스템에 의해 글리콜레이트로 해독됩니다23,24.

인간 적혈구와 간세포에서 글리옥살로부터 옥살산 합성이 체외 실험에서 보고되었습니다24,25,

그러나 후속 연구에서는

이 경로가 체내에서 상대적으로 중요하지 않을 수 있음을 제안했습니다26.

글리옥살은

당뇨병 환자에게서 글리옥살과 옥살산 배설이 증가한다는 점에 따라

신장 결석, 고옥살산혈증 및 당뇨병 사이의 연결 고리로 제안되었습니다23,27.

마지막으로,

글리신은 생리적 조건 하에서 요산산에 기여하는 비율이 5% 미만으로 추정되는

작은 아미노산입니다28 (그림 2).

트립토판, 티로신, 페닐알라닌과 같은 다른 아미노산도

옥살산 전구체로 잠재적이지만,

내인성 옥살산에 대한 기여도는 미미한 것으로 추정됩니다28.

Fig. 2 |. Model of endogenous oxalate synthesis pathways.

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Glyoxylate links several metabolic pathways and is thought to be the principal precursor molecule of endogenous oxalate in healthy humans. Glyoxylate sources include hydroxyproline19, which is derived from collagen metabolism and is metabolized to 4-hydroxy-2-oxoglutarate (HOG) and its reduced form 2,4-dihydroxyglutarate (DHG) via three steps in the mitochondrion; HOG can be converted to glyoxylate by 4-hydroxy-2-oxoglutarate aldolase type 1 (HOGA1). Deficiency of HOGA1 results in primary hyperoxaluria type 3 (PH3) but the exact mechanism by which oxalate accumulates in this condition is not clear4. The accumulation of HOG might inhibit glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which is ubiquitous in cytosol and mitochondria, and converts glyoxylate to glycolate; GRHPR deficiency causes PH2. The amino acid glycine is also converted to glyoxylate by d-amino acid oxidase (DAO) in the peroxisome. Deficiency of liver-specific, peroxisomal alanine–glyoxylate aminotransferase (AGT), which converts glyoxylate to glycine, results in PH1. In addition to glyoxylate, glycolate22 can be derived from sources such as glyoxal, which is a peroxidation product converted to glycolate by the glyoxalase system. Several other processes contribute to glycolate formation, including DNA repair (2-phosphoglycolate is converted to glycolate by phosphoglycolate phosphatase) and fructose or ethylene glycol metabolism (glycolaldehyde is converted to glycolate by aldehyde dehydrogenase). Glycolate is then converted to glyoxylate by liver-specific, peroxisomal glycolate oxidase (GO; also known as HAOX1). Glyoxylate is converted to oxalate by liver-specific lactate dehydrogenase A (LDHA).

Table 1 |.

Major sources of endogenous and exogenous oxalate

SourcePathway(Patho)physiological roles

Endogenous sources
Glycolate	Derived from glyoxal and glyoxylate metabolism, DNA repair, fructose, ethylene glycol22,25	Contributes to 1.3% of oxalogenesis in healthy individuals and 47.3% in PH1; diagnostic marker in PH1 (ref.110); metabolite involved in ethylene glycol poisoning
Hydroxyproline	Derived from collagen catabolism19	Contributes to 15% of urinary oxalate in healthy individuals, and to 18%, 47% and 33% in PH1, PH2 and PH3, respectively19
Glycine	Amino acid28	Contributes to <5% of urinary oxalate in healthy individuals28
Glyoxal	Advanced glycation end-product; also derived from glucose metabolism and lipid peroxidation23,24	Potential link to diabetes23,27
Glyoxylate	Metabolic product generated from 4-hydroxy-2-oxoglutarate, glycolate, glyoxal or glycine19,25	Liver intermediary metabolism linking several metabolic pathways193
Exogenous sources (via excessive ingestion)
Vegetables	Spinach, rhubarb, beets, sweet potato, Chaga mushroom	Oxalate nephropathy
Beverages	Cocoa powder, coffee, some types of tea	Can cause ice (black) tea-induced oxalate nephropathy
Proteins and carbohydrates	Soy, legumes, rice bran, wheatgerm, cornmeal, wholegrain flour	Diet-induced oxalate nephropathy in patients with diabetes194
Fruits	Starfruit, guava, watermelon, raspberries	Starfruit-induced oxalate nephropathy
Seeds and nuts	Chia seeds, peanuts, sesame seeds, almonds, amaranth, hazelnuts, pistachios	Oxalate nephropathy induced by peanut, chia and almond consumption
Supplements	Vitamin C (ascorbic acid)	Vitamin C-induced hyperoxaluria, nephrolithiasis and oxalate nephropathy

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PH1, primary hyperoxaluria 1.

Although endogenous oxalogenesis is incompletely understood, many pathways converge in glyoxylate as the immediate oxalate precursor19,25 (Fig. 2). In a physiologically balanced state, glyoxylate is enzymatically converted to either glycine or glycolate. However, excess glyoxylate is converted into oxalate by liver-specific lactate dehydrogenase A (LDHA)19,20. Exogenous substances that can be metabolized to oxalate include large quantities of vitamin C supplements or of the colourless toxic alcohol ethylene glycol29. Notably, the measurement of oxalate in biological fluids in vitro is complicated by the non-enzymatic conversion of ascorbic acid to oxalate under non-acidic conditions30. This process might also contribute to the elevated plasma oxalate concentrations measured in patients who receive vitamin C supplements30. Ethylene glycol, which is often used as antifreeze owing to its low freezing point, is most commonly ingested with suicidal intent, as a cheap substitute for alcohol or accidentally by children31. After rapid gastrointestinal absorption, the majority of ethylene glycol is metabolized to glycolaldehyde by alcohol dehydrogenase in the liver and then converted to oxalate through several oxidative steps31 (Fig. 2). Extremely elevated plasma and urine concentrations of ethylene glycol and of its metabolites glycolic acid and lactic acid result in severe anion-gap acidosis as well as neurological, cardiopulmonary and kidney impairment31.

Despite a low bioavailability of only 5–15%32,33, dietary oxalate is estimated to contribute to 20–50% of total body oxalate18,34 (Table 1). Oxalate ingestion varies widely across culinary styles and diets in different regions of the world29,35. The typical intake of 100–200 mg/day (with a wide range) in Western diets is presumed to be harmless in patients with normal kidney function29,36. However, numerous studies have reported cases of acute nephropathy induced by the intake of extreme quantities of oxalate-rich foods (for example, starfruit)29. Transit studies suggest that physiological oxalate absorption mainly takes place in the small intestine (and, to a smaller extent, in the stomach and colon) and is modified by the presence of other faecal components37. Oxalate is an ionized conjugate base and is therefore highly susceptible to complexation with divalent cations such as Mg2+ and Ca2+, which bind oxalate in the faecal mass and reduce intestinal absorption14,37.

Based on radioisotope-labelled oxalate infusion studies, >90% of oxalate is estimated to be eliminated via the kidney, unchanged32,38,39. A physiological oxalate excretion of 10–40 mg/day (0.1–0.45 mmol/day) is maintained by a combination of glomerular filtration and net tubular secretion (mainly in the proximal tubule)33,34,40. Only a small fraction of endogenous oxalate is excreted faecally34, but enteric oxalate secretion is upregulated in murine chronic kidney disease (CKD) models, which might help prevent hyperoxalaemia11,41,42.

Epithelial oxalate handling

As discussed earlier, plasma oxalate derives from metabolic production (mainly in the liver) and net gastrointestinal absorption of the dietary oxalate that is ingested under normal conditions14,37,43. When kidney function is normal, oxalate is mainly excreted via the kidney through glomerular filtration and net tubular secretion14,37,43. Thus, steady-state urinary oxalate excretion is in balance with the sum of metabolic oxalate production and net gastrointestinal absorption of dietary oxalate.

Epithelial transport of oxalate mediates its absorption and secretion, and several approaches have been used to characterize the transport pathways involved. For example, studies using membrane vesicles from kidney or intestine identified apical and basolateral membrane anion exchange activities through which oxalate can be reversibly exchanged with anions such as Cl−, OH−, HCO3−, sulfate and formate44–50. Subsequently, cloned transporters from the solute carrier family 26 (SLC26) and SLC4 were found to mediate oxalate transport by some of the same modes of anion exchange. Specifically, functional expression‎ of SLC26 member 1 (SLC26A1), SLC26A2 and SLC26A6 in Xenopus oocytes revealed that each solute carrier is capable of mediating the uptake or efflux of oxalate at high rates above baseline51–53. Functional expression‎ studies also reported detectable oxalate transport through SLC26A3, SLC26A5, SLC26A7, SLC26A8, SLC26A9 and SLC26A11 (refs.54–57); SLC4A1 (also known as AE1) and SLC4A2 (also known as AE2) could also mediate oxalate transport58,59. Of note, determining the physiological roles of these transporters in transepithelial oxalate transport and oxalate homeostasis in vivo has been challenging but studies with knockout mice have provided some insights.

Gastrointestinal tract

Ingested oxalate is absorbed in multiple portions of the gastrointestinal tract, including the stomach, small intestine and large intestine14,37,43. Importantly, this absorption depends on its availability in soluble form because the formation of insoluble oxalate–calcium complexes blocks oxalate absorption14,37,43. Oxalate absorption in the gastrointestinal tract is largely passive (driven by the lumen-to-basolateral concentration gradient) and correlates positively with the amount of soluble oxalate ingested37. Transcellular absorption of oxalate in the stomach due to non-ionic diffusion across the apical membrane (driven by the extreme luminal acidity) is possible but, in the intestine, absorption seems to be predominantly paracellular given that the transepithelial oxalate permeability was similar to that of mannitol, which is a marker of paracellular permeability, across different segments of mouse intestine60. However, the finding that net oxalate absorption occurs in the absence of a passive driving force in studies of mouse ileum and large intestine suggests that transcellular absorption can also occur61 (Fig. 3). Moreover, oxalate absorptive fluxes were reduced in tissues from Slc26a3-null mice, which correlated with a reduced urinary oxalate excretion compared with that of wild-type mice61. Similarly, in wild-type mice with hyperoxaluria induced by an oral oxalate load, a small-molecule inhibitor of SLC26A3 significantly decreased oxalate absorption in the colon and greatly reduced urinary oxalate and oxalate nephropathy in response to oxalate feeding62. These studies not only demonstrated transcellular oxalate absorption but also demonstrated that it is, at least partly, dependent on the expression‎ and activity of the apical membrane transporter SLC26A3. However, although functional expression‎ studies of SLC26A3 demonstrated robust activity as a Cl−–HCO3− exchanger63, the ability of SLC26A3 cloned from multiple species (including humans) to transport oxalate was modest at best54,57,63,64. These findings suggest that SLC26A3 might only contribute to oxalate absorption as a consequence of interactions with other transporters that are present in native tissue but that are not co-expressed with SLC26A3 in the reported functional expression‎ studies.

Fig. 3 |. Oxalate transport in the small intestine.

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Most oxalate absorption in the small intestine occurs passively through the paracellular pathway. Transcellular oxalate secretion is mediated by apical membrane Cl−–oxalate exchange through the transporter solute carrier family 26 member 6 (SLC26A6). The transporter on the basolateral membrane that operates in combination with apical SLC26A6 to mediate transcellular oxalate secretion in the small intestine has not yet been identified.

Transcellular oxalate secretion in multiple intestinal segments opposes oxalate absorption37. The importance of oxalate secretion in limiting net oxalate absorption has been most clearly demonstrated in mouse small intestine. The apical membrane oxalate transporter SLC26A6, which is expressed in the kidneys, pancreas and small intestine, has robust activity as a Cl−–oxalate exchanger and would therefore be predicted to mediate oxalate efflux across cell membranes51,52,65. Accordingly, net oxalate secretion in the duodenum and ileum of Slc26a6-knockout mice was greatly reduced compared with that of wild-type mice66,67. Moreover, Slc26a6-null mice had hyperoxalaemia, which led to hyperoxaluria and urolithiasis; the development of urolithiasis was mouse-strain dependent66,67. Removal of oxalate from the diet greatly reduced both hyperoxalaemia and hyperoxaluria in Slc26a6-null mice, indicating that the source of excess urinary oxalate was predominantly dietary67. These findings support a role for SLC26A6 in back-secreting oxalate that is passively absorbed through tight junctions (Fig. 3). Moreover, a 2021 study suggests that short-chain fatty acids can reduce urinary oxalate levels by upregulating SLC26A6 (ref.68). In a mouse model of CKD11, faecal oxalate excretion increased following induction of CKD, suggesting that intestinal oxalate secretion might be enhanced in response to reduced kidney excretion, yet this increase was absent in Slc26a6-null mice, in which CKD-induced hyperoxalaemia was exacerbated compared with wild-type mice11. Of note, epithelial oxalate secretion can also occur in the mouse large intestine in the absence of SLC26A6, indicating the presence of alternative pathways for apical membrane oxalate secretion, at least in this tissue69. The relevance of intestinal SLC26A6 expression‎ to oxalate homeostasis in humans is thus far only anecdotal. In a patient with subclinical coeliac disease and without fat malabsorption, hyperoxaluria correlated with a markedly reduced expression‎ of SLC26A6 in the small intestine70 whereas, in another patient, enteric hyperoxaluria and nephrolithiasis were associated with a dominant-negative SLC26A6 mutation71. Knockout mice studies also demonstrated a role for SLC26A6 in epithelial oxalate secretion in the salivary gland72.

SLC26A1 is a basolateral sulfate–HCO3−–oxalate anion exchanger that is expressed in several tissues including liver, kidney and intestine52,73–77. The initial report that Slc26a1-null mice had hyperoxalaemia, hyperoxaluria and crystal deposition in the kidneys (similar to the phenotype of Slc26a6-null mice) suggested comparable participation of SLC26A1 and SLC26A6 in intestinal oxalate secretion78. However, subsequent studies found that knockout of Slc26a1 did not impair intestinal oxalate secretion79,80 but rather reduced urinary oxalate excretion80. Biallelic SLC26A1 mutations that impaired the transport function (assayed as sulfate flux) were identified in two patients with calcium oxalate nephrolithiasis, although only one of the patients had hyperoxaluria (mild)81. Consequently, whether loss of function of SLC26A1 can cause substantial hyperoxaluria owing to defective intestinal oxalate secretion remains highly uncertain.

Liver

In addition to variable expression‎ along the gastrointestinal tract, SLC26A6 and SLC26A1 are both expressed in the liver and proximal tubule73,74,82–85. In the liver, the kinetic properties of basolateral SLC26A1 indicate that it is a strong candidate mediator of the efflux of metabolically produced oxalate into the plasma pool77, whereas apical SLC26A6 might contribute to the reported biliary excretion of oxalate86. However, direct evidence for a role of these transporters in mediating oxalate transport in hepatocytes is lacking.

Kidneys

In the kidneys, oxalate is filtered and then undergoes passive absorption and active secretion in the proximal tubule, resulting in net secretion40,87. Net kidney oxalate secretion is dependent on SLC26A6 as the fractional excretion of oxalate decreased from >1 in wild-type mice to <1 in Slc26a6-null mice88. A defect in kidney oxalate secretion in Slc26a6-null mice would therefore be expected to lower urinary oxalate. However, Slc26a6-null mice have hyperoxaluria, suggesting that the aforementioned defect in intestinal oxalate secretion leading to enhanced net oxalate absorption causes sufficient hyperoxalaemia to result in hyperoxaluria even when urinary oxalate secretion is reduced. SLC26A1 is a plausible candidate to mediate basolateral membrane influx of oxalate in combination with apical SLC26A6 to accomplish oxalate secretion in the proximal tubule. However, the kinetic properties of SLC26A1 might preclude it from mediating a substantial influx of oxalate under physiological conditions77. Specifically, based on the relative affinities for HCO3− and oxalate compared with their plasma concentrations, SLC26A1 was predicted to predominantly mediate HCO3− rather than oxalate influx in exchange for intracellular sulfate in the proximal tubule77. No direct evidence of a role for SLC26A1 in mediating oxalate secretion by the proximal tubule is yet available, although the reduced urinary oxalate excretion observed in mice with global knockout of Slc26a1 (ref.80) could hint at a role in kidney oxalate secretion.

Interestingly, human studies demonstrated that, under fasting conditions, fractional excretion of oxalate is ~1, indicating little or no net secretion, although appreciable and rapid net oxalate secretion occurs after ingestion of an oxalate load89. Similarly, substantial net oxalate secretion is observed in patients with elevated plasma oxalate owing to primary hyperoxaluria (PH) but not in patients who form stones without PH90. The mechanisms underlying the upregulation of kidney oxalate secretion in response to acute or chronic oxalate loads remain to be defined. Another aspect of kidney oxalate handling that is incompletely understood is transepithelial transport beyond the proximal tubule. For example, active net absorption of oxalate has been described across the kidney papillary epithelium91. Although this process might not substantially modify urinary oxalate excretion, it might modulate the local interstitial concentration of oxalate and thus affect crystal formation91.

Of note, independently of its role as an oxalate transporter, SLC26A6 might also be an important modifier of the risk of stone formation owing to its ability to interact with and inhibit the activity of the citrate transporter NADC1 (also known as SLC13A2)92. Knockout of Slc26a6 leads to increased activity of NADC1, greater reabsorption of filtered citrate, reduced excretion of urinary citrate and greater risk of calcium nephrolithiasis92.

Role of the microbiome in oxalate homeostasis

Trillions of bacteria colonize the human gut and are involved in diverse functions, including the metabolism of dietary components93,94. These bacteria are increasingly recognized to make important contributions to health and disease. Humans and other mammals lack the enzymes to metabolize oxalate and therefore rely on bacterial degradation to reduce intestinal oxalate, potentially reducing its absorption95. Oxalobacter formigenes is a specialist oxalate degrader and induces colonic oxalate secretion96–98. Epidemiological data have linked antibiotic use with an increase in the incidence of kidney stones99,100, and disturbance of oxalate-degrading microbiota might be a contributing factor101.

Numerous oxalate-degrading microbes have been identified in vitro, but the relative importance of each species in vivo is debated102. A 2021 systematic analysis used high-throughput metagenomic and metatranscriptomic data to investigate bacterial oxalate degradation in vivo. The study showed that the human gut microbiota in healthy adults comprises a diverse community that actively transcribes oxalate-degrading genes12. In healthy individuals, oxalate degradation is primarily performed by O. formigenes, which represents the largest reservoir of oxalate-metabolizing genes at the transcriptional level, greater than all other oxalate-degrading organisms combined, including Escherichia coli, Bifidobacterium spp. and Lactobacillus spp.12 (Fig. 4).

Fig. 4 |. Microbial modulation of oxalate homeostasis.

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Dietary oxalate is degraded by several species of the intestinal microbiota, which can reduce the amount of oxalate available for intestinal absorption. Several bacterial species can degrade oxalate, including Oxalobacter formigenes, Escherichia coli, Bifidobacterium spp. and Lactobacillus spp. O. formigenes also releases a secretagogue that induces oxalate secretion into the gut. Several microbiome-based therapies are being developed to enhance oxalate degradation and reduce oxalate absorption in the gastrointestinal tract. These therapies include supplementation with oxalate-degrading bacterial communities, use of the enzyme oxalate decarboxylase, which metabolizes oxalate, and use of the E. coli Nissle strain, which has been genetically modified to encode the oxalate degradation pathway genes that encode oxalyl-CoA decarboxylase (oxdC) and formyl-CoA:oxalate CoA-transferase (frc).

Most studies linking microbial oxalate metabolism and disease were performed by comparing the gut microbiome of individuals who form kidney stones to that of healthy individuals103–105. For example, analysis of stool cultures showed that the preval‎ence of O. formigenes was lower in individuals who form stones than in healthy individuals106, but this finding was not consistent with subsequent studies that used microbiome sequencing data107,108. Comparing the gut microbiome of individuals who form stones with that of cohabitating healthy adults revealed that healthy individuals had a more extensive microbial network with a higher abundance of connected species centred around O. formigenes, which suggests that they might have a greater capacity for microorganism-driven oxalate metabolism108. Levels of bacterial genes involved in oxalate degradation were also significantly lower in the microbiome of individuals who form stones, which correlated inversely with 24-h oxalate excretion. Similarly, the cumulative abundance of oxalate-degrading bacteria correlated inversely with urinary oxalate103. One study also reported that oxalate-degrading bacteria of three taxa — Enterococcus faecalis, Enterococcus faecium and Bifidobacterium animalis — were less abundant in children with kidney stones than in healthy children105. By contrast, an earlier study showed that patients with hyperoxaluria and kidney stones had a selective enrichment of oxalate-metabolizing bacterial species compared with healthy controls104. More translational and clinical studies are needed to establish the causal relationship between the abundance and function of oxalate-degrading microbiota and urinary oxalate.

Dysregulated oxalate homeostasis

Dysfunction in key steps of physiological oxalate homeostasis can lead to the development of different types of primary and secondary hyperoxaluria (Figs. 1b and 2). Hyperoxaluria is defined as a urinary oxalate excretion of >40–45 mg/day (0.45–0.5 mmol/day), which is associated with various systemic manifestations34,109.

Primary hyperoxaluria

PH comprises autosomal recessive inherited enzyme deficiencies that result in increased hepatic oxalogenesis (Table 2 and Fig. 2; reviewed in ref.110). The diagnosis of PH is primarily based on clinical presentation, including elevated oxalate concentrations in plasma and urine, and can be confirmed with genetic analyses110–113. The most common manifestations of PH include urolithiasis, nephrocalcinosis and urinary tract infections111,112,114. The carrier frequency in the population is estimated at 1:70, and estimates of disease preval‎ence range between 1:58,000 and <3:1,000,000 (ref.113). PH type 1 (PH1) is characterized by a deficiency of alanine–glyoxylate aminotransferase (AGT; encoded by AGXT). More than 200 different AGXT mutations have been identified, with a highly variable genotype–phenotype correlation (see the Human Gene Mutation Database)110. A 2022 study used non-canonical splicing site and copy number variant sequencing to improve the diagnostic accuracy from 26% to 35% in patients with suspected PH115. Of note, another study implemented bioinformatics to identify the microRNA miR-4660, which repressed AGT activity in a subgroup of patients with mutation-negative oxalosis116. Several mutations lead to protein aggregation and mitochondrial mistrafficking of AGT (in humans, AGT needs to be peroxisomal to function properly)117, which results in decreased or diminished enzyme activity118–120. A 2021 report suggested that lack of protein dimerization might be one of the mechanisms underlying AGT mistrafficking121.

Table 2 |.

Primary hyperoxaluria types, diagnostics and manifestations

Type (% of PH cases)Affected enzymeDiagnosticsManifestations

PH1 (refs.110,113) (~80%)	AGT; >200 AGXT mutations described	Clinical presentation, high glycolate (non-specific) and high oxalate in urine and plasma, genetic analysis	Reported age of onset 0.1–53 years113; median urinary oxalate excretion: 1.8 mmol/1.73 m2/day113 (vitamin B6-responsive PH1: 0.94 mmol/1.73 m2/day; vitamin B6-non-responsive PH1: 1.37 mmol/1.73 m2/day111); progression to CKD (>73% of patients) and kidney failure (>50% of patients)114
PH2 (refs.111–113) (7.9–10%)	GRHPR; at least 39 GRHPR mutations described	Clinical presentation, high l-glycerate (non-specific) in urine and high oxalate in plasma and urine, genetic analysis	Reported age of onset 0.6–42 years113; median urinary oxalate excretion: 1.4–1.7 mmol/1.73 m2/day111,113; progression to CKD (50% of patients) and kidney failure (25% of patients)111,112
PH3 (refs.111,113) (8.4–17%)	HOGA1; at least 37 HOGA1 mutations described	Clinical presentation, high 4-hydroxy-2-oxoglutarate or 2,4-dihydroxyglutarate in urine and high oxalate in plasma and urine, genetic analysis	Reported age of onset 0.3–48 years111,113; median urinary oxalate excretion: 1.1–1.16 mmol/1.73 m2/day111,113; progression to CKD (~20% of patients) and kidney failure (one case reported)111,113

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AGT, alanine–glyoxylate aminotransferase; CKD, chronic kidney disease; GRHPR, glyoxylate reductase/hydroxypyruvate reductase; HOGA1, 4-hydroxy-2-oxoglutarate aldolase type 1; PH1, primary hyperoxaluria type 1.

PH type 2 (PH2) accounts for approximately 7.9–10% of PH cases and results from mutations in GRHPR, which encodes the enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR). This enzyme detoxifies glyoxylate to glycolate in the cytosol and mitochondria of hepatocytes111,112. In GRHPR deficiency, glyoxylate and hydroxypyruvate accumulate and are subsequently converted to oxalate and l-glycerate by hepatic LDHA112. At least 39 GRHPR mutations have been described112. PH type 3 (PH3) is caused by a mutation in the gene encoding 4-hydroxy-2-oxoglutarate aldolase type 1 (HOGA1), which is primarily expressed in hepatocyte mitochondria, and accounts for 8.4–17% of PH cases111. HOGA1 catalyses the last step of hydroxyproline metabolism by converting 4-hydroxy-2-oxoglutarate (HOG) into glyoxylate and pyruvate; in HOGA1 deficiency, HOG accumulation has been reported to inhibit GRHPR, resulting in increased oxalate production19. A 2021 report described at least 37 HOGA1 mutations111. The age of disease onset was reportedly earlier in PH3 than in PH2 (ref.113), but several studies report a median age of onset <10 years of age for all three PH types, with a range reaching into late adulthood4,111–113 (Table 2).

The natural history of PH evolves in two phases and their exact timelines depend on the severity and type of the underlying mutation. In the first phase, increased oxalate synthesis is compensated by hyperoxaluria that can reach extremes of up to 1–2 mmol/1.73 m2/day and eventually results in oxalate deposition in the kidney and progressive kidney damage. The second phase unravels as kidney function declines, oxalate excretion becomes insufficient and systemic oxalate deposition ensues, which leads to secondary organ damage4. Although urinary oxalate concentrations have been suggested to correlate positively with PH progression, the most common PH1-causing AGXT mutation, G170R, typically correlates with less severe progression of kidney disease, compared with other PH1-driving AGXT mutations. This difference might be partially explained by the ability to reduce enzyme mistargeting in the G170R genotype through treatment with the cofactor pyridoxine, also known as vitamin B6 (only a few other PH1-causing mutations, such as AGXTF152I, respond to pyridoxine)113. Of note, in the largest study of PH2 to date, the progression of CKD was not associated with genotype or urinary oxalate excretion in an age-corrected analysis112. In this study, patients with PH2 were also less likely than patients with PH1 to present with CKD stage V at diagnosis or before 15 years of age112. In the largest study to date of patients with PH3, PH3 genotype and phenotype did not correlate, and urinary oxalate excretion was not significantly different between vitamin B6-non-responsive PH1, PH2 and PH3 (ref.111). Although kidney failure due to PH3 has been reported113, most studies describe milder kidney disease in patients with PH3 than in those with PH1 or PH2. However, these data might be biased owing to the scarcity of long-term outcome monitoring data and the low penetrance of HOGA1 mutations111.

Secondary hyperoxaluria

Secondary hyperoxalurias are broadly classified as enteric or dietary29. The most common aetiologies of enteric hyperoxaluria are Roux-en-Y gastric bypass and pancreatic insufficiency122; others include malabsorptive conditions, such as short bowel syndrome, coeliac disease, Crohn’s disease and cystic fibrosis, or the use of medications that interfere with intestinal oxalate absorption such as octreotide, which is a somatostatin analogue, or orlistat, which is a lipase inhibitor36. Dietary hyperoxaluria is most often caused by excessive intake of vitamin C or oxalate (discussed above)122.

All types of hyperoxaluria are characterized by three histopathological hallmarks: calcium oxalate crystal deposition, damage to the tubular epithelium and interstitial alterations in the kidney29. However, these patterns might differ between different aetiologies of oxalate nephropathy. For example, in one study, patients with enteric hyperoxaluria were more likely to have tubulointerstitial atrophy and fibrosis, whereas those with non-enteric hyperoxaluria had more pronounced tubular crystal accumulation and interstitial inflammation122. The authors hypothesized that the severity of the kidney outcomes might depend on the latency period following oxalate exposure. However, the mechanisms underlying these differences in the clinical manifestations of enteric and non-enteric hyperoxaluria are still unknown. In vivo findings suggest that crystal deposition is crucial to hyperoxaluria-induced inflammation123.

Chronic kidney disease

In PH, increased endogenous hepatic synthesis of oxalate can lead to extreme plasma oxalate concentrations ranging from 80 μM to 125 μM in advanced stages of disease124. In people with common forms of CKD who do not have PH, plasma or serum oxalate is elevated owing to kidney impairment, especially in patients with kidney failure undergoing dialysis. Nonetheless, plasma or serum oxalate levels in these patients are not as high as those observed in patients with PH, except in patients with Crohn’s disease and ileocecal resections that are treated with maintenance haemodialysis124–126. In these patients, serum oxalate levels correlate with calcium oxalate supersaturation in serum samples and, in certain cases, might reach the serum calcium oxalate supersaturation threshold of 30 μM124,125 (Fig. 1b). Although high plasma oxalate was associated with kidney function decline in primary hyperoxaluria127, data on plasma oxalate and outcomes in more common forms of CKD are currently limited. Nonetheless, although classically described as a risk factor for nephrolithiasis and acute kidney injury owing to intratubular crystal obstruction, the role of oxalate in the pathogenesis of CKD has been further defined in the past few years. Mice fed a diet high in oxalate developed a reproducible CKD phenotype characterized by hypertension, hyperkalaemia, metabolic acidosis, anaemia and hyperphosphataemia; kidney histopathology revealed fibrosis, tubular injury, atubular glomeruli and inflammation128. Epidemiological studies also showed that higher urinary and plasma oxalate levels might be associated with adverse outcomes in kidney disease. A prospective study of adults with common forms of CKD (Chronic Renal Insufficiency Cohort) in the USA showed an independent association between 24-h urinary oxalate excretion and both CKD progression and kidney failure6. Participants in the highest quintile of urinary oxalate excretion had a 33% increased risk of CKD progression and 45% increased risk of kidney failure; 24-h urinary oxalate excretion was also positively associated with greater levels of proteinuria and lower estimated glomerular filtration rate (eGFR)6. Importantly, plasma oxalate levels can be significantly elevated in patients with kidney failure on dialysis because dialysis cannot completely compensate for lost kidney excretion. In a post-hoc analysis of data from a randomized controlled study of patients with diabetes receiving dialysis in Germany, the highest quartile of blood oxalate level was associated with a 40% increased risk of combined cardiovascular events (composite of death from cardiac causes, fatal or non-fatal stroke, or non-fatal myocardial infarction)3. Blood oxalate levels were also significantly associated with sudden cardiac death in secondary analyses.

The role of oxalate as a biomarker in kidney transplant recipients is also unclear. Urinary oxalate excretion was not associated with graft survival129, but the presence of calcium oxalate deposits in allograft biopsy samples might be associated with delayed graft function and decline in allograft function130,131. In 167 kidney transplant recipients followed for 15 years who had plasma oxalate measured 10 weeks after transplantation, plasma levels in the upper quartile were associated with lower long-term patient survival and graft loss; however, these associations were not significant when examining death-censored graft loss132.

Metabolic diseases

Several metabolic diseases are associated with mild hyperoxaluria. For example, individuals with obesity have a high incidence of nephrolithiasis and hyperoxaluria, which correlates with decreased eGFR and increased risk of CKD133. One potential culprit is the pro-inflammatory effect of obesity. Obese mice had a 3.3-fold increase in urinary oxalate excretion (adjusted for creatinine) compared with lean control mice; this increase was accompanied by a significant reduction in intestinal oxalate secretion. This change in secretion might be due to reduced expression‎ of SLC26A6 in obese mice compared with lean mice134. In vitro, pro-inflammatory cytokines suppress Slc26a6 mRNA and protein expression‎134. Another group identified glyoxylate pathway modifications in the hepatocytes of obese mice that led to the hypermethylation and downregulation of Agxt. These changes resulted in a significant increase in hepatic oxalogenesis after hydroxyproline challenge135. Moreover, the pathophysiological overlap between oxalate excretion and diabetes is notable. Individuals with diabetes have an 11% increase in urinary oxalate excretion compared with individuals without diabetes6, which might be partly attributable to elevated concentrations of the oxalate precursors glyoxal and glyoxylate27. Of note, the presence of diabetes was associated with a 44% increase in the risk of a 50% reduction in eGFR or kidney failure among patients with urinary oxalate excretion of ≥16.2 mg/day compared with those with urinary oxalate excretion of <16.2 mg/day6.

Cellular effects of excess oxalate

As discussed earlier, oxalate can form complexes with positively charged minerals. These complexes can grow in size and form oxalate kidney stones that obstruct urinary flow and cause kidney damage133. In addition, oxalate can affect cellular function directly. In vitro, oxalate inhibits the proliferation of kidney epithelial cells, stimulates fibrotic transformation and calcification, and induces cell death128,136. Oxalate might also promote epithelial-to-mesenchymal transformation137. Incubating mouse inner medullary collecting duct cells with oxalate increased expression‎ of mesenchymal markers such as α-smooth muscle actin (also known as aortic smooth muscle actin) and reduced E-cadherin expression‎138. Moreover, oxalate activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in kidney epithelial cells and triggers the release of reactive oxygen species, which promotes oxidative stress139, and has been associated with reduced glutathione and impaired mitochondrial function140.

In addition to the effect of oxalate on epithelial cells, several studies have suggested that oxalate crystals activate inflammatory cells141. For example, oxalate crystals stimulated dendritic cells and macrophages to synthesize and release IL-1β via activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome5,9. Moreover, exposure of human monocytes to a low dose of oxalate crystals disrupted mitochondrial function142. The investigators hypothesized that these biological events might predispose to recurrent stone formation. A subsequent study revealed that macrophages treated with oxalate also had decreased cellular bioenergetics, mitochondrial complex I and IV activity, and ATP levels compared with control cells143. These cells had impaired metabolism, redox homeostasis and cytokine signalling, which compromised their antibacterial response in vitro and increased the risk of bacterial infection143.

A 2021 study demonstrated that the glycine-to-oxalate ratio in blood is lower in both patients and mice with atherosclerosis than in controls10. This effect was due to suppressed activity of AGT, similar to what is observed in patients with PH1. Mice deficient for AGT and apolipoprotein E (ApoE) had increased atherosclerosis compared with mice that were only deficient for ApoE, which was accompanied by the induction of hepatic pro-atherogenic pathways associated with increased inflammation (based on changes in cytokine and chemokine signalling). Macrophages from AGT-deficient mice exposed to oxalate also showed mitochondrial dysfunction and superoxide accumulation, which led to increased release of the pro-atherogenic CC chemokine ligand 5 (CCL5). The observed phenotype could be reversed with AGXT overexpression‎. One of the limitations of the study was the high concentration of oxalate used to stimulate macrophages; although non-cytotoxic, a concentration of 750 μM is still several times higher than that observed in the blood of patients, even in those with impaired kidney excretion. Nevertheless, this study suggests a mechanistic link between increased plasma oxalate and atherosclerosis.

These observations support previous studies suggesting that oxalate might promote atherosclerosis. In vitro, supraphysiological extracellular oxalate concentrations inhibit the proliferation and induce oxidative stress in endothelial cells8,144. Moreover, the oxalate crystal-induced release of pro-inflammatory cytokine IL-1α from monocytes has been associated with increased risk of atherosclerotic cardiovascular events in patients with acute myocardial infarction or CKD, possibly by promoting leukocyte–endothelial adhesion and inflammation through the expression‎ of vascular cell adhesion molecule 1 on endothelial cells7. Importantly, future clinical studies will need to address whether oxalate concentrations observed in humans with hyperoxalaemia can have the same effects as exposure to supraphysiological amounts of oxalate in vitro.

Therapies for oxalate dysregulation

Many conservative treatment options are available for mild types of hyperoxaluria, including the hyperoxaluria observed in patients with nephrolithiasis. These therapeutic approaches are based on the prevention of urinary calcium oxalate crystallization and might be as simple as adequate hydration, which has proven useful for the prevention of kidney stones; hyperhydration is recommended in patients with PH1 (>3 l/1.73 m2 body surface area/day)110,145,146. In addition, a phase I trial of tolvaptan has shown promise in reducing urinary calcium oxalate, calcium phosphate and uric acid supersaturation by increasing urine volume147. A similar effect was reported for thiazide diuretics, whose hypocalciuric and hypermagnesiuric properties might reduce calcium oxalate kidney stone formation148. Citrate administration has also been suggested to prevent the formation of kidney stones149,150. Moreover, a 2016 study showed that citrate and hydroxycitrate can dissolve calcium oxalate monohydrate crystals in vitro150. Even at concentrations three times lower than that of the solute, citrate and hydroxycitrate adsorption to oxalate crystal surfaces led to the localized dissolution of calcium and oxalate ions with comparable efficacy150. Of note, a 2022 report from a phase II clinical trial suggested that lemon juice might be a viable alternative to pharmaceutical citrate formulations, which are frequently discontinued by patients owing to adverse gastrointestinal effects151.

Targeting oxalate absorption

In enteric hyperoxaluria, several therapeutic approaches are based on the binding of oxalate in the intestine to prevent hyperabsorption. As described earlier, the bioavailability of oxalate is influenced by gut health and the presence of different faecal components (for example, cations, fat or medication)14,36,37. Consequently, direct supplementation of calcium and fat limitation (which has been reported to increase intestinal calcium–oxalate binding) might decrease oxalate hyperabsorption146,152. Based on the same principle of limiting oxalate absorption, the bile acid-binding resin cholestyramine reduced colonic oxalate absorption in rats by blocking the binding of oxalate to bile acids and subsequent intestinal reabsorption but its efficacy was variable in humans153. However, in a case study of a patient with short bowel syndrome, cholestyramine reduced both faecal fat and urinary oxalate excretion154. Calcium-containing phosphate binders, which might promote the formation of calcium–oxalate complexes, have also been suggested as potential oxalate-lowering agents155. However, current KDIGO guidelines recommend limiting the use of calcium-based phosphate binders in patients with CKD stages G3a–G5D owing to the increased mortality risk associated with these compounds compared with non-calcium-based phosphate binders156. Following encouraging experimental results, the non-calcium-based phosphate binder lanthanum carbonate is currently being tested in a phase III trial in patients with secondary hyperoxaluria and nephrolithiasis157. Treatment with the non-calcium phosphate binder sevelamer hydrochloride for 1 week also led to a non-significant reduction in urinary oxalate in an open-label study of patients with enteric hyperoxaluria158. Of note, a 2021 quantum chemical study suggested that trivalent cations, such as Fe3+, Al3+ or La3+, rather than divalent cations as well as the chemical element neodymium, might be interesting oxalate-binding candidates for preclinical testing159.

Microbiome-related therapies

The effect of microbiome manipulation on oxalate homeostasis using single organisms or bacterial communities has been eval‎uated extensively in animal models and a few human studies (Fig. 4). Consequently, several therapeutic formulations are based predominantly on the oxalate-degrading capacity of certain bacteria. In rodent models of hyperoxaluria, O. formigenes colonization consistently led to a reduction in urinary oxalate97,160. In addition to oxalate degradation, O. formigenes produced a secretagogue, yet to be characterized, that induces oxalate secretion into the gut97. However, although the O. formigenes derivatives OC3 and OC5 (lyophilized O. formigenes in enteric-coated capsules, the latter with a higher viable cell count) are well tolerated by humans, they had mixed efficacy in phase I–III trials161,162.

Colonization with Bifidobacterium and Lactobacillus species also reduced urinary oxalate in animals97,163. Oxadrop, which is a probiotic composed of Lactobacillus acidophilus, Lactobacillus brevis, Streptococcus thermophilus and Bifidobacterium infantis, resulted in a short-lived reduction in urinary oxalate in patients with enteric hyperoxaluria164. Importantly, none of these trials eval‎uated bacterial viability in the gut following their ingestion. Other bacterial strains currently being investigated in early-stage trials include Nov-001, UBLG-36 and SYNB8802. Nov-001 is a therapeutically engineered microbial combination product that includes NB1000S, which is an oxalate-degrading bacterium, and NB2000P, a prebiotic control molecule used to control the abundance of NB1000S; a phase II trial is currently recruiting patients with enteric hyperoxaluria after an encouraging phase I study165. UBLG-36, which is a Lactobacillus paragasseri strain, is highly effective in degrading oxalate in vitro166. Finally, orally administered SYNB8802, which is a synthetic oxalate-degrading E. coli Nissle strain, significantly reduced urinary oxalate in mice and non-human primates. In silico modelling based on human gastrointestinal physiology predicted that this strain could lower urinary oxalate by up to 71% in patients with enteric hyperoxaluria167.

Whole microbial transfers have also been investigated as potential approaches to modulate oxalate metabolism. In rats, a faecal transplant from a mammalian herbivore whose whole microbiome community is adapted to degrading high amounts of dietary oxalate led to lower urinary and faecal oxalate levels compared with the ingestion of oxalate-degrading isolates168; the decrease in urinary oxalate persisted for 9 months after the transfer169. Similarly, a faecal transplant from conventional rats, which have a gut microbiome similar to that of humans, into germ-free mice reduced urinary oxalate170. This transfer caused a reduction in SLC26A6 expression‎ in the kidney and colon and increased expression‎ in the caecum. To date, no studies have eval‎uated the effect of microbiome community transfer in humans.

Instead of administering bacterial strains, several investigators have attempted direct supplementation with oxalate decarboxylase (OxDC), which is the enzyme used by O. formigenes to degrade oxalate. A double-blind randomized controlled crossover trial of a proprietary OxDC in healthy individuals showed a 24% urinary oxalate reduction compared with placebo171. In a phase I trial, recombinant OxDC cloned from Bacillus subtilis significantly reduced urinary oxalate in patients with Roux-en-Y gastric bypass (mean 66.3 mg/day, standard deviation (SD) 28.0 mg/day at baseline; 44.5 mg/day, SD 23.7 mg/day at 4 weeks; P = 0.018), but this reduction was not significant in patients with idiopathic calcium oxalate stone formation (43.2 mg/day, SD 5.9 mg/day at baseline; 32.3 mg/day, SD 3.2 mg/day at 4 weeks; P = 0.06)172. Another OxDC formulation (ALLN-177) significantly reduced urinary oxalate excretion in patients with preserved kidney function, including a phase III trial in patients with enteric and idiopathic hyperoxaluria (urinary oxalate excretion for all participants 77.7 mg/day, SD 55.9 mg/day at baseline; 63.7 mg/day, SD 40.1 mg/day after 4 days of treatment; P < 0.05)173. In a pilot study of patients with CKD and severe enteric hyperoxaluria, ALLN-177 reduced plasma oxalate by 29% from baseline174. However, a phase III study of ALLN-177 in patients with enteric hyperoxaluria over a 4-week period demonstrated that the reduction in urinary oxalate was only 14.3% greater than that achieved with placebo175. Determining whether a modest lowering of urinary oxalate has a clinical benefit with regard to stone disease progression will require long-term follow-up studies.

Treatments for primary hyperoxaluria

Therapeutic options for primary hyperoxaluria have traditionally been scarce and the only curative option was combined liver and kidney transplantation110. Vitamin B6 supplementation reduces hepatic oxalate production by restoring AGT activity and reducing mitochondrial mistargeting in patients with PH1 owing to specific AGXT mutations, such as G170R or F152I, in vivo and clinically118–120. More specifically, in vitro studies suggest that the monomer form of AGT is unstable and prone to misfolding and aggregation, which impedes peroxisomal transport; vitamin B6 promotes dimerization, which appears to stabilize the enzyme and may facilitate proper peroxisomal transport119,121.

In vitamin B6-non-responsive PH1, therapeutic approaches aim to inhibit the key hepatic enzymes that produce oxalate (glycolate oxidase, also known as hydroxyacid oxidase, and LDHA), for example, by using RNA interference (reviewed in refs.110,176). RNA interference is an innate mechanism of most eukaryotic cells that allows for sequence-specific inhibition of gene expression‎ via non-coding double-stranded RNA fragments (20–25 bp long)177,178. These small interfering RNAs (siRNAs) are recognized by an RNA-induced silencing complex, which induces degradation of the target mRNA177,178. Exogenously synthesized siRNAs have been celebrated as a major therapeutic breakthrough that allows the potent repression of disease-causing genes. However, researchers are still improving chemical siRNA modifications to optimize organ-specific drug delivery and reduce off-target effects, including unintended immune stimulation177,178.

siRNA-based Lumasiran is the first EMA-approved and FDA-approved PH1-specific treatment and must be administered subcutaneously110. This treatment silences the glycolate oxidase gene (HAO1) and was shown to reduce urinary oxalate by 64.1–70% compared with placebo in phase III trials of adults and children; the first results from another phase III trial (NCT04152200) are currently undergoing quality control179,180. The resulting increase in plasma glycolate concentrations did not appear to be associated with adverse events179, in contrast to the severe acidosis observed in patients with ethylene glycol poisoning leading to elevated plasma glycolate concentrations181. Case reports demonstrate tolerability and efficacy as early as the second week of life, and suggest that pre-treatment with Lumasiran might enable the use of isolated kidney transplantation (rather than combined with liver transplantation) in PH1 (refs.182,183). Nedosiran, another subcutaneously administered siRNA-based drug, silences LDHA and was shown to reduce urinary oxalate excretion by 68% after multiple doses184. The medication was also successfully used to reduce dialysis frequency and defer combined liver and kidney transplantation in a patient with PH1 (ref.184); in a phase I study, nedosiran also normalized urinary oxalate excretion in one-third of patients with PH2 (ref.185).

Gene editing has also been used to knock out Hao1 and Ldha in animal studies. The CRISPR–Cas9 system was delivered by an adenovirus vector to knock out Hao1 in Agxt1−/− mice, which are used as a PH1 model; this treatment normalized urinary oxalate excretion and prevented nephrocalcinosis without toxicity186. Administration of an Ldha-targeting adenovirus-coupled CRISPR–Cas9 system to rats with a PH1-causing AgxtD205N mutation reduced LDHA expression‎ by 50% and significantly lowered urinary oxalate excretion and kidney calcium oxalate deposits after an ethylene glycol challenge compared with controls; the treatment also caused mild changes in hepatic glycolytic and triglyceride pathways187. Another study of Agxt1−/− mice treated with a single dose of an adenovirus-coupled CRISPR–Cas9 system reduced LDHA expression‎ by >95% and reduced urine oxalate to levels similar to those of wild-type animals after ethylene glycol exposure without significant toxic off-target effects or hepatotoxicity188. In a PH3 model (Hoga1−/− mice), the same CRISPR–Cas9 cleavage vector system was slightly less effective than in the PH1 model but also induced a significant reduction in LDHA expression‎ and urine oxalate levels were comparable to those of wild-type animals after hydroxyproline challenge188. Of note, none of the mice in the PH3 model developed kidney damage upon hydroxyproline exposure (in contrast to PH1 mice challenged with ethylene glycol)188. More research is needed to test the applicability of these findings and potential off-target effects in humans.

Immune modulation

Immune modulation is another potential approach for treating oxalate-related diseases. For example, inhibition of NLRP3 inflammasome activation might reduce cleavage of the pro-inflammatory cytokines IL-1β and IL-18 via caspase 1 and inhibit inflammatory cell death (pyroptosis)189. The microRNA miR-22-3p binds to NLRP3 as well as to long intergenic non-protein-coding RNA 339, which is highly upregulated in human kidney proximal epithelial cells treated with calcium oxalate monohydrate. This microRNA reduced calcium oxalate-induced inflammasome activation and pyroptosis in human kidney proximal epithelial cells in vitro190. In a study of male hyperoxaluric rats, inhibition of the transient receptor potential vanilloid 1 channel, which functions upstream of NLRP3, mitigated reactive oxygen species-induced NLRP3 activation and calcium oxalate-induced nephropathy but did not reduce hyperoxaluria191. Other NLRP3 inhibitors with promising murine in vivo results include the diarylsulfonylurea-based CP-456773, which mitigates crystal-induced kidney fibrosis192.

Conclusions

An abundance of evidence supports a pathological role of excess oxalate when the balance between oxalate intake, production and excretion is disrupted. Overall, 50–80% of oxalate is endogenously produced and derived from amino acid and carbohydrate metabolism, whereas 20–50% derives from dietary intake and is absorbed predominantly in the small intestine. Epithelial transport of oxalate via anion exchange mediates oxalate absorption and secretion along the gastrointestinal tract, in the liver and in the kidneys, with SLC26A6 being the best-established oxalate transporter. The human gut harbours important microbial networks that help regulate oxalate levels, most notably the specialist oxalate degrader bacterium O. formigenes. Inherited enzyme defects that lead to increased endogenous oxalate production or increased intestinal absorption of oxalate observed in secondary hyperoxaluria can lead to oxalate nephropathy and kidney failure. Moreover, elevated urinary oxalate concentrations are associated with CKD progression, and increased plasma oxalate levels correlate with cardiovascular mortality in patients with kidney failure requiring dialysis. In addition, the presence of metabolic diseases, such as obesity and diabetes mellitus, might increase the risk of developing nephrolithiasis and hyperoxaluria or losing kidney function in the setting of high oxalate excretion. At a cellular level, oxalate inhibits proliferation, stimulates fibrotic transformation and calcification, leads to the upregulation of pro-atherogenic and inflammatory pathways by promoting inflammasome activation and oxidative stress, and induces cell death.

Therapies for oxalate dysregulation aim to re-establish the physiological components necessary to maintain oxalate homeostasis (Table 3). Modulation of free oxalate availability in urine and the gut has been used as a successful strategy to mitigate nephrolithiasis and secondary hyperoxaluria. One promising approach on the horizon are allogeneic transfers of oxalate-degrading microbial communities to reduce urinary oxalate. By contrast, treatments for PH focus on restoring the function of enzymes involved in hepatic oxalogenesis such as AGT, for example, through vitamin B6 supplementation in select PH subtypes, or inhibition of oxalate-producing LDHA or glycolate oxidase through siRNAs or CRISPR–Cas9 technology. Finally, immune modulation is another potential approach to prevent and treat the severe consequences of oxalate-related diseases.

Table 3 |.

Promising novel therapeutic options targeting oxalate dysregulation

StrategyPrimary indicationClinical evidenceExperimental evidence only

Prevention of urinary calcium oxalate crystallization	Nephrolithiasis	Hyperhydration110,145,146, tolvaptan147, thiazides148, (hydroxy)citrate149,150, lemon juice151,a, active Agropyron repens extract195	NA
Prevention of intestinal hyperabsorption	All types of hyperoxaluria (by limiting oxalate intake); secondary hyperoxaluria	Limited oxalate intake109,196, calcium146,152, limited fat intake146,152, cholestyramine153,154,a, lanthanum carbonate157, sevelamer158	NA
Administration of oxalate-degrading microbes	Different types of hyperoxaluria	OC5 (refs.161,162,197), Nov-001 (ref.165)	Lactobacillus paragasseri UBLG-36 (ref.166), SYNB8802 (ref.167)
Oxalate decarboxylase supplementation	Secondary hyperoxaluria	Proprietary oxalate decarboxylase171, recombinant oxalate decarboxylase cloned from Bacillus subtilis172, ALLN-177 (refs.173,174)	NA
Ensure proper folding and/or relocation of AGT	Primary hyperoxaluria type 1	Vitamin B6 (refs.118–120,198,199)	NA
Protein inhibition or knockout of genes encoding oxalate-producing hepatic enzymes	Primary hyperoxaluria type 1	Lumasiran179,180,182,183, nedosiran184	CRISPR–Cas9 (refs.186–188)
Inhibition of NLRP3 and pro-inflammatory cytokines	Experimental only	NA	miR-22-3p190, CP-456773/CRID3/MCC950 (ref.192)

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AGT, alanine–glyoxylate aminotransferase; NA, not applicable; NLRP3, NACHT, LRR and PYD domains-containing protein 3.

a

Ongoing clinical trial.

Further research is needed to better characterize the role and therapeutic potential of different transporters from the SLC26 anion exchanger family and microbial communities in maintaining oxalate homeostasis. Important open questions include the extent to which oxalate is causally involved in the progression of CKD and CKD-related cardiovascular disease as well as effective therapeutic strategies to achieve sustained lowering of oxalate concentrations. Additionally, more detailed studies of the inflammatory pathways through which oxalate exerts its detrimental effects will likely reveal new treatment options. Robust clinical studies are an essential next step to translate in vitro, in vivo and observational clinical findings into the human setting and leverage this knowledge for the prevention and treatment of oxalate-related conditions in clinical practice.

Key points.

• Oxalate homeostasis is maintained through a combination of endogenous biosynthesis, exogenous supply, and renal and faecal excretion. Disruptions to these mechanisms caused by genetic mutations (primary hyperoxaluria) or increased oxalate absorption (secondary hyperoxaluria) result in oxalate nephropathy.

• Solute carrier family 26 member 6 anion transporter has an important role in the maintenance of oxalate homeostasis by facilitating transcellular oxalate secretion in the intestine (in contrast to paracellular absorption).

• Among several oxalate-degrading bacteria in the human gut microbiota, Oxalobacter formigenes represents a major reservoir of oxalate-metabolizing genes.

• Oxalate inhibits kidney epithelial cell proliferation, promotes fibrotic transformation, calcification and atherosclerosis, and induces cell death. These pathological pathways are probably mediated, at least in part, through NLRP3 inflammasome stimulation and mitochondrial disruption.

• Urinary oxalate excretion is independently associated with the progression of chronic kidney disease and kidney failure. Elevated blood oxalate is also associated with increased risk of cardiovascular events, in particular sudden cardiac death.

• Oxalate-balancing treatment options include O. formigenes analogues and oxalate decarboxylase supplements, small interfering RNA therapeutics that target oxalate-producing hepatic enzymes, and experimental CRISPR–Cas9 approaches and anti-inflammatory strategies.

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Acknowledgements

The work of F.K. was supported by the German Research Foundation (DFG) — KN1148/4-1 and Project-ID 394046635, SFB 1365.

Competing interests

F.K. reports personal fees from Allena, Oxthera, Sanofi, Fresenius Medical Care, Alnylam Pharmaceuticals, Advicenne, Medice and Zai, and grant support from Alnylam and Dicerna Pharmaceuticals. S.W. reports personal fees from Public Health Advocacy Institute, CVS, Roth Capital Partners, Kantum Pharma, Mallinckrodt, Wolters Kluewer, GE Health Care, GSK, Allena Pharmaceuticals, Mass Medical International, Barron and Budd (versus Fresenius), JNJ, Venbio, Strataca, Takeda, Cerus, Pfizer, Bunch and James, Harvard Clinical Research Institute (also known as Baim Institute for Clinical Research), Oxidien, Sironax, Metro Biotechnology, Biomarin, Bain and Regeneron. L.N. reports personal fees from Oxthera, Dicerna, Federation Bio, Allena, Novome and Synlogic. All other authors declare no competing interests.

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