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ReviewVolume 79, Issue 5p717-727May 2022

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Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review

Nathalie Demoulin1,3 nathalie.demoulin@uclouvain.be ∙ Selda Aydin2,3 ∙ Valentine Gillion1,3 ∙ Johann Morelle1,3 ∙ Michel Jadoul1,3

Affiliations & Notes

•  

Abstract

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.

과옥살뇨증은 

간에서 옥살산염이 과다 생성되는 글리옥실산 대사 장애(일차성 과옥살뇨증) 또는 

장에서 옥살산염 흡수 증가(이차성 과옥살뇨증)로 인해 발생합니다. 

과옥살뇨증은 

소변 내 칼슘 옥살산염의 과포화와 결정 형성을 유발하여 

요로 결석증과 신장 실질에 칼슘 옥살산염 결정이 침착되는 

옥살산염 신장병을 유발할 수 있습니다. 

과옥살뇨증과 옥살산 신장병을 유발하는 병리생리학적 메커니즘에 대한 이해가 상당히 진전되었습니다. 다행히도, 일차성 과옥살뇨증 환자들에게 새로운 치료 방법이 곧 등장할 전망입니다. 이차성 과옥살뇨증 환자들은 오랜 기간 동안 과옥살뇨증을 유발하는 조건을 가지고 있는 경우가 많습니다. 이는 탈수증과 같은 급성 신장 손상의 유발 요인이 작용한다는 사실을 시사합니다. 현재 이러한 환자들에 대한 표준 치료법은 근본적인 원인 관리, 다량의 수분 섭취, 칼슘 보충제 사용 등을 포함합니다. 전반적으로, 최적의 관리를 통해 결과를 개선할 수 있기 때문에, 고요산혈증과 관련된 옥살산 신장병을 신속하게 인식하는 것이 중요합니다.

Index Words

1. Calcium oxalate crystals
2. chronic kidney disease (CKD)
3. crystallopathies
4. fat malabsorption
5. kidney failure
6. lumasiran
7. nephrolithiasis
8. oxalate
9. oxalate nephropathy
10. oxalosis
11. primary hyperoxaluria
12. review
13. secondary hyperoxaluria
14. steatorrhea
15. urolithiasis

Introduction

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, leading to a condition termed oxalate nephropathy. We discuss the progress made in the understanding of intestinal and renal handling of oxalate and crystal-induced kidney damage and review the diagnosis and management of primary and secondary hyperoxaluria.

소개
과옥살뇨증은 간에서 옥살산염이 과다 생성되는 글리옥실산 대사 장애(일차성 과옥살뇨증) 또는 장에서 옥살산염 흡수 증가(이차성 과옥살뇨증)로 인해 발생합니다. 과옥살뇨증은 소변 내 칼슘 옥살산염의 과포화와 결정 형성을 유발하여 요로 결석증과 신장 실질에 칼슘 옥살산염 결정이 침착되는 원인이 되며, 이로 인해 옥살산염 신장병이라는 질환이 발생합니다. 우리는 옥살산염과 결정에 의한 신장 손상의 장과 신장에서의 처리 과정에 대한 이해의 진전 사항에 대해 논의하고, 일차 및 이차성 고옥살뇨증의 진단과 관리에 대해 검토합니다.

Oxalate Metabolism and Measurement

Oxalate, the ionized form of oxalic acid, originates from both hepatic production as part of normal metabolism and absorption by the bowel from food (Fig 1). Hepatic synthesis of oxalate from glyoxylate contributes to 60%-80% of plasma oxalate1,2 (Fig 2). Dietary sources rich in oxalate include leafy vegetables, nuts, tea, and fruits rich in vitamin C.3,4 Average daily oxalate intake is approximately 80-130 mg.5,6 Only 5% to 15% of dietary oxalate is normally absorbed because oxalate bound to calcium in the gut is eliminated in the stools and oxalate is degraded by intestinal bacteria, such as Oxalobacter formigenes1,7 (Fig 1).

옥살산 대사 및 측정

옥살산은

옥살산의 이온화된 형태로,

간에서 정상적인 대사 과정의 일부로 생성되거나

음식에서 장으로 흡수되어 생성됩니다(그림 1).

글리옥실산으로부터의 옥살산 합성은

혈장 옥살산 농도의 60%-80%를 차지합니다1,2(그림 2).

옥살산이 풍부한 식품에는

잎채소, 견과류, 차, 비타민 C가 풍부한 과일 등이 있습니다.3,4

옥살산 섭취량은 하루 평균 80-130mg입니다. 5,6

일반적으로 식이성 옥살산염의 5%에서 15%만이 흡수되는데,

이는 장에서 칼슘에 결합된 옥살산염이 대변으로 배설되고

옥살산염이 Oxalobacter formigenes1,7(그림 1)와 같은 장내 세균에 의해

분해되기 때문입니다.

Figure viewer

Figure 1 Causes and consequences of secondary hyperoxaluria. Secondary hyperoxaluria results from increased dietary oxalate or oxalate precursor intake, fat malabsorption, and decreased intestinal oxalate degradation due to alterations in gut microbiota. Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to nephrolithiasis, oxalate nephropathy, and possibly CKD progression.

그림 1 이차성 고옥살뇨증의 원인과 결과. 

이차성 고옥살뇨증은 

식이성 옥살산염 또는 옥살산염 전구체의 섭취 증가, 

지방 흡수 장애, 

장내 미생물총의 변화로 인한 장내 옥살산염 분해 감소로 인해 발생합니다. 

고옥살뇨증은 

칼슘 옥살산염의 소변 내 과포화와 결정 형성을 유발하여 

신장결석증, 옥살산염 신장병증, 그리고 가능하면 

CKD의 진행에 기여할 수 있습니다.

Based on information in Sayer et al,1 Ermer et al,7 Hoppe et al,5 and Aronson et al.79 Abbreviations: CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system.

Figure viewer

Figure 2 Glyoxylate metabolism in the hepatocyte and enzymatic deficiencies in primary hyperoxaluria. Primary hyperoxaluria types 1 and 2, associated with peroxisomal AGT and cytosolic GRHPR deficiency respectively, result in accumulation of glyoxylate, which is converted to oxalate by LDH. Primary hyperoxaluria 3 is caused by a defect in HOGA in mitochondria; mechanisms leading to increased oxalate levels are not well-defined. GO catalyses the conversion of glycolate to glyoxylate and glyoxylate to oxalate. RNA interference (RNAi)-based drugs targeting GO and LDH are potential therapies for patients with PH1.

그림 2 간세포에서의 글리옥실산 대사 및 일차성 고옥살뇨증의 효소 결핍. 

일차성 고옥살뇨증 유형 1과 유형 2는 각각 퍼옥시좀 AGT와 세포질 GRHPR 결핍과 관련이 있으며, 글리옥실산이 축적되어 LDH에 의해 옥살산으로 전환됩니다. 일차성 고옥살뇨증 3은 미토콘드리아의 HOGA 결함에 의해 발생하며, 옥살산염 수치를 증가시키는 메커니즘은 잘 알려져 있지 않습니다. GO는 글리콜레이트를 글리옥실레이트로, 글리옥실레이트를 옥살레이트로 전환하는 과정을 촉진합니다. RNA 간섭(RNAi) 기반의 약물은 GO와 LDH를 표적으로 삼아 PH1 환자를 위한 잠재적 치료법으로 사용될 수 있습니다.

Abbreviations: AGT, alanine-glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase–hydroxypyruvate reductase; HOGA, 4-hydroxy-2-oxoglutarate aldolase; LDH, lactate dehydrogenase. Based on information in Cochat and Rumsby,23 Hoppe,2 and Devresse et al.22

Oxalate is absorbed in the gut via paracellular passive transport, but there is also strong evidence of active intestinal absorption

and secretion via transcellular oxalate anion exchangers of the solute-linked carrier 26 (SCL26) family. The relative contribution of oxalate absorption involving paracellular and transcellular pathways and secretion determines the overall net oxalate movement across the intestine.8 SLC26A1 and SCL26A6 exchangers are expressed in the basolateral and apical membrane of enterocytes, respectively, allowing oxalate secretion into the intestinal lumen. SLC26A3 is an apical oxalate transporter mediating oxalate uptake.1,7 Studies suggest a remarkable adaptive capacity of the intestine to either actively absorb or secrete oxalate in response to local and systemic inputs integrated through the endocrine and autonomic nervous systems.8 Cholinergic regulation inhibits oxalate uptake through reduced expression‎ of SCL26A6 in human cell lines.8-10 A purinergic signaling system also regulates oxalate transport across digestive epithelia.11,12 In murine chronic kidney disease (CKD) models, Slc26a6-mediated enteric oxalate secretion is critical in lowering the body burden of oxalate.13

Plasma oxalate does not have any known function in the human body and is rapidly excreted by the kidney via glomerular filtration and tubular secretion. Both mechanisms are critical in regulating plasma oxalate levels.14,15 SCL26A6 is also located at the apical membrane of the proximal tubule and actively transports oxalate into the urinary filtrate. SLC26A1 is localized to the basolateral membrane of the tubular cell and is thought to reduce urinary oxalate secretion.1,7

Urinary oxalate excretion in healthy adults is influenced by dietary intake, and levels exceeding 40-45 mg/d (500 μmol/d) define hyperoxaluria.16 Oxaluria may also be quantified using the oxalate to creatinine ratio on a spot urine sample.17 Studies have shown a good correlation between spot level and 24-hour excretion, with no significant diurnal pattern of oxalate excretion.18,19 In individuals with stages 4 and 5 CKD, urinary oxalate excretion decreases and plasma oxalate starts to rise.20 Plasma oxalate levels are used to monitor primary hyperoxaluria patients with CKD and on dialysis before transplantation.21,22 Plasma oxalate levels should be <30 μmol/L at the end of each dialysis session because this is the threshold value for oversaturation of plasma calcium oxalate.5

However, accurate measurement of plasma oxalate concentration is challenging. Prompt acidification or freezing of samples and storage at −80°C until acidification is required to prevent conversion of plasma ascorbate to oxalate.20 Moreover, plasma oxalate levels do not correlate well with estimated glomerular filtration rate (eGFR) and show significant intraindividual variation in patients with primary hyperoxaluria.21

옥살산염은

세포간 수동 수송을 통해 장에서 흡수되지만,

용질 결합 운반체 26(SCL26) 계열의 세포간 옥살산염 음이온 교환기를 통한

능동적인 장내 흡수 및 분비라는 강력한 증거도 있습니다.

세포간 및 세포간 경로를 통한 옥살산염 흡수와 분비의 상대적 기여도는

장을 통한 전체적인 옥살산염 이동량을 결정합니다.8

SLC26A1과 SCL26A6 교환기는 각각 장내 세표의 기저막과 정단막에서 발현되어, 장 내강으로 옥살산염을 분비할 수 있도록 합니다. SLC26A3은 옥살산염 흡수를 매개하는 정단 옥살산염 수송체입니다.1,7 연구에 따르면 내분비 및 자율 신경계를 통해 통합된 국소 및 전신 입력에 반응하여 장이 옥살산염을 적극적으로 흡수하거나 분비하는 놀라운 적응 능력을 가지고 있는 것으로 나타났습니다. 8 콜린성 조절은 인간 세포주에서 SCL26A6의 발현 감소로 옥살산염 흡수를 억제합니다.8-10 퓨린성 신호 전달 시스템은 소화기 상피를 통한 옥살산염 수송을 조절합니다.11,12 쥐의 만성 신장 질환(CKD) 모델에서, Slc26a6에 의한 장내 옥살산염 분비는 체내의 옥살산염 부담을 낮추는 데 매우 중요합니다.13

플라스마 옥살산염은 인체에서 알려진 기능이 없으며, 사구체 여과와 세뇨관 분비를 통해 신장에서 빠르게 배설됩니다. 이 두 가지 메커니즘은 혈중 옥살산염 수치를 조절하는 데 매우 중요합니다.14,15 SCL26A6은 근위 세뇨관의 정단막에 위치하며, 옥살산염을 소변 여과액으로 활발하게 운반합니다. SLC26A1은 세뇨관 세포의 기저막에 위치하며, 소변 내 옥살산염 분비를 감소시키는 것으로 여겨집니다.1,7

건강한 성인의 옥살산 배설은 식이 섭취의 영향을 받으며, 40-45mg/d(500μmol/d)를 초과하는 수준은 고옥살산뇨증으로 정의됩니다.16  옥살산뇨증은 소변 샘플의 요산 대 크레아티닌 비율을 사용하여 정량화할 수도 있습니다.17 연구에 따르면 옥살산 수준과 24시간 배설량 사이에는 좋은 상관관계가 있으며, 옥살산 배설량에 대한 일주 패턴은 유의미하지 않습니다. 18,19 4단계와 5단계의 만성콩팥병 환자의 경우, 소변 내 옥살산 배설량이 감소하고 혈장 내 옥살산 수치가 증가하기 시작합니다.20 혈장 내 옥살산 수치는 만성콩팥병 환자 중 일차성 고옥살뇨증 환자나 이식 전 투석 환자의 상태를 모니터링하는 데 사용됩니다.21,22 혈장 내 옥살산 수치는 각 투석 세션이 끝날 때 30μmol/L 미만이어야 합니다. 이는 혈장 내 칼슘 옥살산이 과포화되는 임계치이기 때문입니다.5

그러나, 플라즈마 옥살산염 농도를 정확하게 측정하는 것은 어렵습니다. 플라즈마 아스코르베이트가 옥살산염으로 전환되는 것을 방지하기 위해 시료의 신속한 산성화 또는 동결과 산성화가 필요할 때까지 -80°C에서 보관해야 합니다.20 또한, 플라즈마 옥살산염 수치는 추정 사구체 여과율(eGFR)과 잘 상관되지 않으며, 원발성 고옥살뇨증 환자의 경우 개인 간에 상당한 차이가 있습니다.21

Primary Hyperoxaluria

Primary hyperoxaluria types 1, 2, and 3 are rare autosomal recessive inherited disorders of glyoxylate metabolism caused by pathogenic variants in AGXT, GRHPR, or HOGA1, respectively (Fig 2).2,23 The inability to metabolize glyoxylate leads to excessive hepatic production of oxalate and subsequent accumulation in various organs, including the kidney.2,23 Massive urolithiasis and/or calcium oxalate deposition in the renal parenchyma impairs kidney function and oxalate elimination. When the eGFR drops to ≤30-45 mL/min/1.73 m2, plasma oxalate increases, and oxalate may deposit in bone, kidneys, skin, retina, and the cardiovascular and central nervous systems. This dramatic condition is referred to as systemic oxalosis.2,22,23 Primary hyperoxaluria type 1 is the most common and severe form, generally leading to kidney failure during the first 3 decades of life. However, in some patients the condition is not diagnosed until adulthood with occasional or recurrent urolithiasis as the only clinical manifestations. The Gly170Arg and Phe152Ile variants in AGXT (a glycine to arginine substitution at amino acid 170 and a phenylalanine to isoleucine substitution at amino acid 152, respectively) are associated with adult-onset hyperoxaluria and with a less severe prognosis, partly due to the response to pyridoxine.23 Primary hyperoxaluria types 2 and 3 are generally milder, although patients with type 2 may present with CKD caused by recurrent urolithiasis.2,23

Prompt diagnosis of primary hyperoxaluria is essential to prevent downstream complications. Unfortunately, up to 50% of patients have advanced CKD or kidney failure at diagnosis, and approximately 10% are diagnosed after disease recurrence on a kidney allograft.2 As a result, the possibility of primary hyperoxaluria should be systematically considered among children with kidney stones or nephrocalcinosis and in adults with recurrent calcium oxalate stones. Patients with primary hyperoxaluria usually have a higher urinary oxalate excretion (>100 mg/d, >1.0 mmol/1.73 m2/d, or 1,000 μmol/d) than those with secondary hyperoxaluria (50-100 mg/d, 0.5-1.0 mmol/1.73 m2/d, or 500-1,000 μmol/d).2 In children, age-specific reference ranges for spot urinary oxalate to creatinine ratios are used.2,17 Measures of plasma oxalate level may be helpful in patients with CKD stage 3b because they generally increase only when the eGFR is below 30 mL/min/1.73 m2 in patients with CKD from other etiologies. The definitive diagnosis of primary hyperoxaluria is achieved by molecular genetic testing.2,23

The conservative therapeutic options in primary hyperoxaluria include massive fluid intake (tube or gastrostomy feeding in infants), calcium oxalate crystallization inhibitors, and vitamin B6 (pyridoxine) in primary hyperoxaluria type 1.23 To date, liver transplantation is the only established “curative” therapy to correct the metabolic defect contributing to excessive endogenous oxalate formation.2,22,23 Liver-kidney transplantation (simultaneously or sequentially) is the current standard of care in patients with primary hyperoxaluria type 1 and CKD. It should ideally be performed before the development of systemic oxalosis and related complications.22-24 Indeed, outcomes after kidney transplantation are improved by a substantial residual kidney function and by the absence of major systemic oxalate load.23 Oliguria should be avoided in the peritransplant period; in this respect, minimizing the risk of acute tubular necrosis of the graft may impact the choice of donor. In patients with kidney failure awaiting transplantation, intensive hemodialysis strategies limit systemic oxalate accumulation.22,23

New promising therapeutic agents are under investigation and are expected to dramatically influence the management and outcomes of patients with primary hyperoxaluria. Lumasiran is a RNA interference (RNAi)-based therapy that blocks the synthesis of oxalate glycolate oxidase and reduces oxidation of glycolate to glyoxylate, the immediate precursor of oxalate (Fig 2). In the phase 3 ILLUMINATE-A study, patients with primary hyperoxaluria type 1 receiving lumasiran showed a significant reduction in urinary oxalate excretion after 6 months of treatment in comparison with the placebo group.25 Two additional phase 3 trials testing the efficacy and safety of lumasiran are ongoing: ILLUMINATE-B (ClinicalTrials.gov identifier www.clinicaltrials.gov/ct2/show/NCT03905694) and ILLUMINATE-C (clinicaltrials.gov/ct2/show/NCT04152200).22 The US Food and Drug Administration and European Medicines Agency have recently approved lumasiran for the treatment of children and adults with primary hyperoxaluria type 1. Nedosiran, a RNAi therapy targeting lactate dehydrogenase and reducing conversion of glyoxylate to oxalate, is being tested in a phase 3 study (clinicaltrials.gov/ct2/show/NCT04042402). If these emerging therapies are confirmed to be efficient and safe in patients on dialysis and in kidney graft recipients, liver transplantation may perhaps no longer be required in the future.22

Secondary HyperoxaluriaCauses of Secondary Hyperoxaluria

Secondary hyperoxaluria results from (1) increased dietary oxalate or oxalate precursor intake, (2) fat malabsorption, and (3) decreased intestinal oxalate degradation due to alterations in gut microbiota (Fig 1; Box 1). Hyperoxaluria has been associated with increased intake of nuts, tea, Averrhoa carambola (star fruit) and bilimbi, rhubarb, chaga mushroom, spinach, and “green smoothies” and “juicing.”4 Ascorbic acid (vitamin C), ethylene glycol, naftidrofuryl oxalate (a vasodilator), and methoxyflurane (an anesthetic agent) all are precursors of oxalate, and excessive intake or exposure may lead to hyperoxaluria (Fig 3). Fat malabsorption from various causes (pancreatic disorders, Roux-en-Y bypass surgery, short bowel disease, Crohn disease, use of orlistat) leads to steatorrhea, calcium binding by fatty acids in the intestinal lumen, increased intestinal absorption of free oxalate, and higher ileal and colonic permeability to oxalate. Secondary hyperoxaluria may also be multifactorial. For example, cystic fibrosis leads to hyperoxaluria via malabsorption due to exocrine pancreatic insufficiency, defects in oxalate exchangers, and microbiota perturbations associated with frequent antibiotic use.26,27

Figure viewer

Figure 3 Oxalate precursors and metabolic pathways.

Box 1

Causes of Secondary Hyperoxaluria and Oxalate Nephropathy

aData mostly obtained from murine models.

Increased intestinal oxalate absorption

•

Chronic pancreatitis

•

Pancreatectomy

•

Use of orlistat (lipase inhibitor)

•

Roux-en-Y gastric bypass

•

Small bowel resection

•

Crohn’s disease

•

Celiac disease

•

Cystic fibrosis

•

Use of somatostatin analogue

Increased dietary oxalate or precursor intake

•

Rhubarb, Averrhoa carambola (star fruit), Averrhoa bilimbi, tea, nuts, “juicing”

•

Vitamin C, ethylene glycol, methoxyflurane, naftidrofuryl oxalate

Decreased intestinal bacterial oxalate degradation

•

Antibiotic use

Others

•

Obesity, genetic variations in oxalate transporters?a

Obesity and the metabolic syndrome are also associated with calcium oxalate nephrolithiasis.28,29 Obese mice show local and systemic inflammation, which contributes to reduced active transcellular oxalate secretion into the bowel via anion exchanger Slc26a6 and enhanced gastrointestinal paracellular absorption of oxalate.29-31 Obesity-associated cholinergic activity also leads to Slc26a6 inhibition.10 Increased dietary ingestion of oxalate and alterations in intestinal microbiota may further contribute to obesity-associated hyperoxaluria.29,31 Moreover, urinary excretion of oxalate is higher in individuals with diabetes mellitus.3 Plasma levels of glyoxylate and glyoxal (a protein glycation product), potential precursors of oxalate, are higher in diabetic patients, possibly contributing to hyperoxaluria.3

Secondary hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation,16 contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy5 (Fig 1). In contrast to primary forms of the disease, characterized by a high systemic oxalate load, secondary hyperoxaluria only leads to extrarenal deposition of oxalate in very rare cases, such as in severe Crohn disease.14

Secondary Hyperoxaluria and Urolithiasis

Hyperoxaluria is the main risk factor for calcium oxalate urolithiasis.5 Supersaturation of calcium oxalate is 10 times more dependent on a rise in urinary oxalate than on an equimolar rise of urinary calcium concentration.5 Urinary oxalate excretion correlates with the risk of developing a kidney stone event.32 In patients with malabsorption, fluid loss and a low urinary pH and citrate level also contribute to the pathogenesis of urolithiasis.27,32 A meta-analysis of 12 observational studies showed a significantly higher risk of stone formation after Roux-en-Y gastric bypass surgery with a pooled relative risk of 1.79 (95% CI, 1.54-2.10).33 Similarly, a recently published review reported a stone incidence ranging from 2% to 38% in patients with malabsorptive states other than after bariatric surgery.27

The risk of calcium oxalate urolithiasis is also associated with intestinal microbiota composition. Healthy oxalate homeostasis in the gastrointestinal tract involves a collaborative effort between numerous bacterial species. In fecal samples from healthy individuals, metagenomics studies reveal a network of bacterial taxa co-occurring with Oxalobacter formigenes, which are less represented in urinary stone formers.34 This would explain why the absence of O formigenes is not causative of stone disease and why colonization with the bacteria failed to reduce urinary oxalate excretion in interventional studies.35 Similarly, children who are calcium oxalate stone formers have fewer oxalate-degrading and butyrate-forming bacterial taxa in the gut, leading to hyperoxaluria. Butyrate maintains the gut mucosal barrier and regulates intestinal SLC26 oxalate transporters.36

In mice, Slc26a1 gene deletion causes a reduction in intestinal secretion of oxalate, leading to hyperoxalemia and hyperoxaluria.37 Human SLC26A1 mutations may presumably lead to urolithiasis via similar mechanisms.1 Additionally, polymorphisms of SLC26A6 in humans may explain accelerated lithogenesis in distinct populations.16,38

Secondary Hyperoxaluria and Oxalate Nephropathy

Oxalate nephropathy is a severe condition resulting from deposition of calcium oxalate crystals in kidney tissue, which causes tubular-interstitial injury and fibrosis, acute kidney injury (AKI), and/or CKD26,39-41 (Fig 4). Most investigators have used the following diagnostic criteria for oxalate nephropathy: (1) progressive kidney disease, (2) oxalate crystal deposition with tubular injury and interstitial nephritis, and (3) exclusion of other etiologies of kidney disease (aside from vascular and/or diabetes-associated nephropathy). A hyperoxaluria-enabling condition should ideally also be identified26,39-41 (Box 2).

Figure viewer

Figure 4 Oxalate nephropathy, kidney biopsy sample. (A) Intratubular translucent polyhedral or rhomboid crystals (black arrows) on light microscopy (hematoxylin and eosin stain, original magnification, ×20). (B) Crystals shown as birefringent under polarized light (original magnification, ×5). Biopsy also shows acute tubular injury and mild interstitial inflammation.

Box 2

Definition of Oxalate Nephropathy

1.

Progressive kidney disease.

2.

Deposition of calcium oxalate crystals (birefringent on polarized light) within tubular epithelial cells, tubular lumens, and less frequently in the interstitium, associated with tubular injury and interstitial nephritis.

3.

Exclusion of other causes of kidney disease (apart from nonspecific microvascular lesions and/or diabetes-associated glomerular lesions).

4.

Ideally, a hyperoxaluria enabling-condition should be identified.

The preval‎ence of oxalate nephropathy is unknown. We recently reported 22 cases (1%) of oxalate nephropathy out of 2,265 consecutive native kidney biopsies performed during a 9-year period.40 Table 1 shows the clinical characteristics and outcomes of patients with oxalate nephropathy reported in 4 case series and 1 systematic review.26,39-42 Upon presentation, most patients had hypertension, diabetes, and/or a history of CKD. The latter may result from past subclinical deposition of oxalate crystals or represent a predisposing factor because of reduced excretion of oxalate.40

Nasr et al, 2008a,39Cartery et al, 2011a,41Lumlertgul et al, 201826Buysschaert et al, 202040Yang et al, 202042

Table 1

Published Cases Series of Secondary Oxalate Nephropathy

Values for categorical variables are given as n (%) or count; for continuous values as mean. Abbreviations: NA, not available (or too few numbers); OxN, oxalate nephropathy; RAAS, renin-angiotensin-aldosterone system; UPCR, urinary protein-creatinine ratio.

a

Included in the systematic review by Lumlertgul et al.26

b

Patients with unknown causes of oxalate nephropathy and those with short duration of exposure (<30 days) to hyperoxaluria-enabling conditions were excluded.

c

Quantitative data from 57 case reports of oxalate nephropathy not reported in Lumlertgul et al.26

d

Twenty-one of 22 patients with available clinical data.

e

Patients with other causes of CKD such as lupus nephritis were included.

f

Some patients had 2 identified hyperoxaluria-enabling conditions.

g

No systematic gastrointestinal and/or genetic workup reported.

h

Normal value ≤ 45 mg/d.

i

Normal value < 32 mg/g.

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Approximately two-thirds of the patients have malabsorption-associated hyperoxaluria.26,40 We found that chronic pancreatitis and gastric bypass were the most common causes of oxalate nephropathy (48%).40 Of note, Lumlertgul et al26 excluded patients with a short duration of exposure (<30 days) to the hyperoxaluria-enabling conditions (ie, vitamin C and oxalate-rich foods). Interestingly, hyperoxaluria-enabling conditions (ie, malabsorptive states) may be long standing; we reported the development of oxalate nephropathy a mean of 8 years after gastric bypass in 5 patients and 1 and 8 years after orlistat initiation in 2 patients.40 This suggests that the combination of the hyperoxaluria-enabling condition with an additional factor or trigger may lead to crystal formation and kidney damage40,4143,44 (Fig 1). Factors such as acute dehydration, diuretic use, inflammation, antibiotic use, or high dietary oxalate intake may increase the urinary oxalate concentration. Renin-angiotensin-aldosterone system (RAAS) blocker use is also highly preval‎ent in patients presenting with oxalate nephropathy and may favor oxalate crystal-associated kidney injury via the reduction of glomerular filtration fraction.39-41

Clinical presentation of oxalate nephropathy varies across the spectrum of AKI, AKI on CKD, and CKD. Patients present with kidney failure in most cases (mean serum creatinine level of 4.9-8.0 mg/dL). Moderate to profound hypocalcemia was reported in 9 of 12 patients with oxalate nephropathy associated with chronic pancreatitis and may evoke the diagnosis.41 Kidney biopsy shows variable degrees of acute tubular necrosis, interstitial nephritis, and chronic damage. In addition, a substantial proportion of patients have glomerular changes (mostly glomerulosclerosis, associated or not with diabetes). The prognosis of oxalate nephropathy is variable, with approximately half of patients rapidly reaching kidney failure. The outcome may be more favorable in patients presenting with oxalate nephropathy secondary to acute ingestion of high amounts of dietary oxalate.4

Calcium oxalate crystals are most commonly found in proximal and distal tubules in the cortex. They are deposited within tubular lumens, tubular epithelial cells, and less frequently in the interstitium.45 Calcium oxalate crystals are strongly birefringent on polarized light, unlike calcium phosphate crystals46 (Fig 4). Of note, scarce calcium oxalate crystals may be found in tubules in patients with other causes of kidney damage, especially in the setting of reduced eGFR.31,39,41,42 We thus recently suggested adding an oxalate crystal to glomerulus ratio of ≥0.25 in the definition of oxalate nephropathy. Indeed, we found that this ratio separates patients with oxalate nephropathy from those with other well-documented kidney diseases and scarce calcium oxalate crystals.40 Further studies are needed to validate this criterion for distinguishing oxalate nephropathy from nonspecific oxalate deposition. It is also worth noting that although the term “nephrocalcinosis” is often used to refer to calcium salt deposits in kidney tissue, it should probably be used for calcium phosphate and not for calcium oxalate deposition.47

Studies have shown that different crystals such as calcium oxalate, uric acid, and monoclonal light chains share cellular and molecular mechanisms leading to kidney damage, such as stimulation of the NLRP3 inflammasome, a multiprotein oligomer that triggers interleukin-1β (IL-1β)-induced inflammation.48-51 In mice, Nlrp3 deletion successfully protects from progressive kidney failure secondary to ingestion of a diet high in soluble oxalate.51 Nlrp3 inhibition in hyperoxaluric mice protects against calcium oxalate deposition and CKD via a shift in the phenotype of renal macrophages, promoting anti-inflammatory rather than proinflammatory and profibrotic responses. The IL-1 inhibitor anakinra did not show such a protective effect, suggesting that Nlrp3 contributes to calcium oxalate deposition–induced kidney fibrosis independently from IL-1-mediated tissue injury.52

The characteristics of crystal deposition condition the clinical presentation. Acute supersaturation, rapid crystal formation, direct and indirect kidney epithelial cytotoxicity, and inflammation-driven cell necrosis lead to acute kidney damage. By contrast, ongoing mild supersaturation generating subacute crystal plug formation in distal tubules or collecting ducts leads to CKD.48 Crystal deposition is a potent driver of kidney fibrosis, leading to loss of kidney function.48,49

Hyperoxaluria and Progression of CKD

Given the potential nephrotoxicity of oxalate at high levels, Waikar et al53 hypothesized that a higher urinary oxalate, even within the reference range, would be associated with a higher risk of CKD progression. They tested this hypothesis in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective multicenter cohort study of risk factors for cardiovascular disease, progression of CKD, and mortality in patients with mild to moderate CKD. Among 3,123 participants, they showed that higher versus lower 24-hour urinary oxalate excretion (at the 40th percentile) was independently associated with a 32% higher risk of CKD progression and 37% higher risk of kidney failure.53

The association between hyperoxaluria and faster decline in eGFR was also shown in a small cohort of patients with chronic pancreatitis.54 Similarly, previous studies have suggested that calcium oxalate deposition in kidney graft biopsies may be associated with lesser graft function beyond the early posttransplant period.55,56 Urinary oxalate excretion may thus be a potential risk factor for progression in common forms of CKD. Likewise, it has been suggested that urinary oxalate may be a potential mediator of CKD development and progression in individuals with diabetes or obesity.3 Altogether, if these results are confirmed, the question of whether lowering urinary oxalate excretion could be beneficial in slowing CKD progression would need to be addressed.

Management of Secondary Hyperoxaluria and Oxalate Nephropathy

Treatment should be initiated rapidly, starting with high fluid intake16,27,57 (Table 2). The goal is to obtain a daily urine output in excess of 2-3 liters in order to reduce urinary supersaturation with oxalate. Dietary measures to reduce intestinal oxalate absorption include a low-oxalate, low-fat, and normal calcium diet.27 Additionally, calcium supplements are given orally to reduce the bioavailability of intestinal oxalate and its absorption.27,58 Crystallization inhibitors such as citrate may also be used.59 Importantly, all studies performed with these interventions were performed on small numbers of individuals for a limited periods of time, often without control groups or randomization.60

TreatmentRationaleSupporting evidence

High fluid intake (urine output >2-3 L/d)	Reduces urine calcium oxalate supersaturation.	Reduces stone formation.67,68
Low-oxalate diet	Reduces bioavailability of intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies; caveat: comparisons were based on a low-oxalate diet compared to a very-high-oxalate diet.60,69,70
Low-fat diet	Reduces intestinal oxalate absorption (by increasing bioavailability of intestinal calcium).	Reduces urinary oxalate excretion in small studies.70,71
Normal-calcium diet	Avoid low-calcium diets, which lead to more free intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies.69,72
Calcium supplements	Reduce bioavailability of intestinal oxalate and its absorption.	Reduces urinary oxalate excretion but may lead to hypercalciuria.72-74 Calcium citrate may be more bioavailable than calcium carbonate.75
Cholestyramine	Binds intestinal bile acids, reduces diarrhea, and binds oxalate in vitro.	Studies show contradicting results.70,73,76
Oxalobacter formigenes administration	Increases intestinal oxalate degradation.	Reduces urinary oxalate excretion in rat model61,77 and plasma oxalate levels in dialysis patients with primary hyperoxaluria (phase 2 study).35
Oxalate decarboxylase	Degrades intestinal oxalate.	Reduces urinary oxalate excretion in rat model78 and in phase 3 pilot study in humans.62
NLRP3-specific inflammasome inhibitor	Reduces crystal-induced kidney damage.	Reduces calcium-oxalate crystal-induced kidney fibrosis in mouse model.63

Table 2

Current and Potential Therapies of Secondary Hyperoxaluria

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The therapeutic options currently being tested include oral administration of intestinal bacteria and/or enzymes capable of degrading oxalate. O formigenes administration has been shown to reduce urinary oxalate excretion in animal models with enteric hyperoxaluria.61 In humans, this strategy has only been tested in patients with primary hyperoxaluria.35 Oxalate decarboxylase, an oxalate-degrading enzyme, was shown in a pilot phase 3 open-label study to reduce urinary oxalate excretion among 16 patients with both secondary hyperoxaluria and a history of kidney stones.62 The results will need to be confirmed in the phase 3 follow-up randomized controlled trial. A better understanding of the molecular mechanisms of crystal nephropathies may also lead to the development of targeted therapies.48 As previously mentioned, a NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.63

A diagnostic workup is fundamental to treating the underlying cause of hyperoxaluria. Hyperoxaluria-enabling conditions may be long standing but paucisymptomatic. We have shown, for example, that chronic pancreatitis may frequently be diagnosed only after oxalate nephropathy, even in kidney transplant recipients.40,41,64 Morpho-constitutional analysis of kidney stones, combining stereomicroscopy and Fourier-transform infrared spectroscopy, may help in determining the cause of hyperoxaluria.65 Dietary hyperoxaluria may be difficult to identify because oxalate content is not provided by food manufacturers and food tables often report conflicting data on oxalate content.60 In patients with hyperoxaluria and/or oxalate nephropathy of unknown etiology, primary hyperoxaluria must not be overlooked (see the previous section).66

Treatment of the underlying cause of secondary hyperoxaluria includes withdrawal of oxalate-rich foods or precursors, pancreatic enzyme therapy, intensification of Crohn disease therapy, and in some cases reversal of gastric bypass. Identification and management of the cause of secondary hyperoxaluria is also important to minimize the risk of recurrence of oxalate nephropathy after kidney transplantation. Therapeutic considerations concerning patients with secondary hyperoxaluria on dialysis and during the peritransplantation period are beyond the scope of this review. In addition, further studies are needed to determine the clinical significance of hyperoxaluria in asymptomatic patients with hyperoxaluria-enabling conditions in order to determine the subset with the greatest likelihood of deriving benefit from treatment aimed at preventing renal complications.

Conclusions

Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and associated kidney damage. Prompt recognition and management of primary and secondary hyperoxaluria is crucial. Fortunately, novel targeted therapeutic approaches are on the horizon for patients with primary hyperoxaluria.

Article InformationAuthors’ Full Names and Academic Degrees

Nathalie Demoulin, MD, Selda Aydin, MD, PhD, Valentine Gillion, MD, Johann Morelle, MD, PhD, and Michel Jadoul, MD.

Support

None.

Financial Disclosure

The authors declare that they have no relevant financial interests.

Peer Review

Received March 28, 2021. Eval‎uated by 3 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor and a Deputy Editor. Accepted in revised form July 27, 2021.

References

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Sayer, J.A.

Progress in understanding the genetics of calcium-containing nephrolithiasis

J Am Soc Nephrol. 2017; 28:748-759

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ReviewVolume 79, Issue 5p717-727May 2022

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Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review

Nathalie Demoulin1,3 nathalie.demoulin@uclouvain.be ∙ Selda Aydin2,3 ∙ Valentine Gillion1,3 ∙ Johann Morelle1,3 ∙ Michel Jadoul1,3

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Abstract

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.

Index Words

1. Calcium oxalate crystals
2. chronic kidney disease (CKD)
3. crystallopathies
4. fat malabsorption
5. kidney failure
6. lumasiran
7. nephrolithiasis
8. oxalate
9. oxalate nephropathy
10. oxalosis
11. primary hyperoxaluria
12. review
13. secondary hyperoxaluria
14. steatorrhea
15. urolithiasis

Introduction

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, leading to a condition termed oxalate nephropathy. We discuss the progress made in the understanding of intestinal and renal handling of oxalate and crystal-induced kidney damage and review the diagnosis and management of primary and secondary hyperoxaluria.

Oxalate Metabolism and Measurement

Oxalate, the ionized form of oxalic acid, originates from both hepatic production as part of normal metabolism and absorption by the bowel from food (Fig 1). Hepatic synthesis of oxalate from glyoxylate contributes to 60%-80% of plasma oxalate1,2 (Fig 2). Dietary sources rich in oxalate include leafy vegetables, nuts, tea, and fruits rich in vitamin C.3,4 Average daily oxalate intake is approximately 80-130 mg.5,6 Only 5% to 15% of dietary oxalate is normally absorbed because oxalate bound to calcium in the gut is eliminated in the stools and oxalate is degraded by intestinal bacteria, such as Oxalobacter formigenes1,7 (Fig 1).

Figure viewer

Figure 1 Causes and consequences of secondary hyperoxaluria. Secondary hyperoxaluria results from increased dietary oxalate or oxalate precursor intake, fat malabsorption, and decreased intestinal oxalate degradation due to alterations in gut microbiota. Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to nephrolithiasis, oxalate nephropathy, and possibly CKD progression. Based on information in Sayer et al,1 Ermer et al,7 Hoppe et al,5 and Aronson et al.79 Abbreviations: CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system.

Figure viewer

Figure 2 Glyoxylate metabolism in the hepatocyte and enzymatic deficiencies in primary hyperoxaluria. Primary hyperoxaluria types 1 and 2, associated with peroxisomal AGT and cytosolic GRHPR deficiency respectively, result in accumulation of glyoxylate, which is converted to oxalate by LDH. Primary hyperoxaluria 3 is caused by a defect in HOGA in mitochondria; mechanisms leading to increased oxalate levels are not well-defined. GO catalyses the conversion of glycolate to glyoxylate and glyoxylate to oxalate. RNA interference (RNAi)-based drugs targeting GO and LDH are potential therapies for patients with PH1. Abbreviations: AGT, alanine-glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase–hydroxypyruvate reductase; HOGA, 4-hydroxy-2-oxoglutarate aldolase; LDH, lactate dehydrogenase. Based on information in Cochat and Rumsby,23 Hoppe,2 and Devresse et al.22

Oxalate is absorbed in the gut via paracellular passive transport, but there is also strong evidence of active intestinal absorption and secretion via transcellular oxalate anion exchangers of the solute-linked carrier 26 (SCL26) family. The relative contribution of oxalate absorption involving paracellular and transcellular pathways and secretion determines the overall net oxalate movement across the intestine.8 SLC26A1 and SCL26A6 exchangers are expressed in the basolateral and apical membrane of enterocytes, respectively, allowing oxalate secretion into the intestinal lumen. SLC26A3 is an apical oxalate transporter mediating oxalate uptake.1,7 Studies suggest a remarkable adaptive capacity of the intestine to either actively absorb or secrete oxalate in response to local and systemic inputs integrated through the endocrine and autonomic nervous systems.8 Cholinergic regulation inhibits oxalate uptake through reduced expression‎ of SCL26A6 in human cell lines.8-10 A purinergic signaling system also regulates oxalate transport across digestive epithelia.11,12 In murine chronic kidney disease (CKD) models, Slc26a6-mediated enteric oxalate secretion is critical in lowering the body burden of oxalate.13

Plasma oxalate does not have any known function in the human body and is rapidly excreted by the kidney via glomerular filtration and tubular secretion. Both mechanisms are critical in regulating plasma oxalate levels.14,15 SCL26A6 is also located at the apical membrane of the proximal tubule and actively transports oxalate into the urinary filtrate. SLC26A1 is localized to the basolateral membrane of the tubular cell and is thought to reduce urinary oxalate secretion.1,7

Urinary oxalate excretion in healthy adults is influenced by dietary intake, and levels exceeding 40-45 mg/d (500 μmol/d) define hyperoxaluria.16 Oxaluria may also be quantified using the oxalate to creatinine ratio on a spot urine sample.17 Studies have shown a good correlation between spot level and 24-hour excretion, with no significant diurnal pattern of oxalate excretion.18,19 In individuals with stages 4 and 5 CKD, urinary oxalate excretion decreases and plasma oxalate starts to rise.20 Plasma oxalate levels are used to monitor primary hyperoxaluria patients with CKD and on dialysis before transplantation.21,22 Plasma oxalate levels should be <30 μmol/L at the end of each dialysis session because this is the threshold value for oversaturation of plasma calcium oxalate.5

However, accurate measurement of plasma oxalate concentration is challenging. Prompt acidification or freezing of samples and storage at −80°C until acidification is required to prevent conversion of plasma ascorbate to oxalate.20 Moreover, plasma oxalate levels do not correlate well with estimated glomerular filtration rate (eGFR) and show significant intraindividual variation in patients with primary hyperoxaluria.21

Primary Hyperoxaluria

Primary hyperoxaluria types 1, 2, and 3 are rare autosomal recessive inherited disorders of glyoxylate metabolism caused by pathogenic variants in AGXT, GRHPR, or HOGA1, respectively (Fig 2).2,23 The inability to metabolize glyoxylate leads to excessive hepatic production of oxalate and subsequent accumulation in various organs, including the kidney.2,23 Massive urolithiasis and/or calcium oxalate deposition in the renal parenchyma impairs kidney function and oxalate elimination. When the eGFR drops to ≤30-45 mL/min/1.73 m2, plasma oxalate increases, and oxalate may deposit in bone, kidneys, skin, retina, and the cardiovascular and central nervous systems. This dramatic condition is referred to as systemic oxalosis.2,22,23 Primary hyperoxaluria type 1 is the most common and severe form, generally leading to kidney failure during the first 3 decades of life. However, in some patients the condition is not diagnosed until adulthood with occasional or recurrent urolithiasis as the only clinical manifestations. The Gly170Arg and Phe152Ile variants in AGXT (a glycine to arginine substitution at amino acid 170 and a phenylalanine to isoleucine substitution at amino acid 152, respectively) are associated with adult-onset hyperoxaluria and with a less severe prognosis, partly due to the response to pyridoxine.23 Primary hyperoxaluria types 2 and 3 are generally milder, although patients with type 2 may present with CKD caused by recurrent urolithiasis.2,23

Prompt diagnosis of primary hyperoxaluria is essential to prevent downstream complications. Unfortunately, up to 50% of patients have advanced CKD or kidney failure at diagnosis, and approximately 10% are diagnosed after disease recurrence on a kidney allograft.2 As a result, the possibility of primary hyperoxaluria should be systematically considered among children with kidney stones or nephrocalcinosis and in adults with recurrent calcium oxalate stones. Patients with primary hyperoxaluria usually have a higher urinary oxalate excretion (>100 mg/d, >1.0 mmol/1.73 m2/d, or 1,000 μmol/d) than those with secondary hyperoxaluria (50-100 mg/d, 0.5-1.0 mmol/1.73 m2/d, or 500-1,000 μmol/d).2 In children, age-specific reference ranges for spot urinary oxalate to creatinine ratios are used.2,17 Measures of plasma oxalate level may be helpful in patients with CKD stage 3b because they generally increase only when the eGFR is below 30 mL/min/1.73 m2 in patients with CKD from other etiologies. The definitive diagnosis of primary hyperoxaluria is achieved by molecular genetic testing.2,23

The conservative therapeutic options in primary hyperoxaluria include massive fluid intake (tube or gastrostomy feeding in infants), calcium oxalate crystallization inhibitors, and vitamin B6 (pyridoxine) in primary hyperoxaluria type 1.23 To date, liver transplantation is the only established “curative” therapy to correct the metabolic defect contributing to excessive endogenous oxalate formation.2,22,23 Liver-kidney transplantation (simultaneously or sequentially) is the current standard of care in patients with primary hyperoxaluria type 1 and CKD. It should ideally be performed before the development of systemic oxalosis and related complications.22-24 Indeed, outcomes after kidney transplantation are improved by a substantial residual kidney function and by the absence of major systemic oxalate load.23 Oliguria should be avoided in the peritransplant period; in this respect, minimizing the risk of acute tubular necrosis of the graft may impact the choice of donor. In patients with kidney failure awaiting transplantation, intensive hemodialysis strategies limit systemic oxalate accumulation.22,23

New promising therapeutic agents are under investigation and are expected to dramatically influence the management and outcomes of patients with primary hyperoxaluria. Lumasiran is a RNA interference (RNAi)-based therapy that blocks the synthesis of oxalate glycolate oxidase and reduces oxidation of glycolate to glyoxylate, the immediate precursor of oxalate (Fig 2). In the phase 3 ILLUMINATE-A study, patients with primary hyperoxaluria type 1 receiving lumasiran showed a significant reduction in urinary oxalate excretion after 6 months of treatment in comparison with the placebo group.25 Two additional phase 3 trials testing the efficacy and safety of lumasiran are ongoing: ILLUMINATE-B (ClinicalTrials.gov identifier www.clinicaltrials.gov/ct2/show/NCT03905694) and ILLUMINATE-C (clinicaltrials.gov/ct2/show/NCT04152200).22 The US Food and Drug Administration and European Medicines Agency have recently approved lumasiran for the treatment of children and adults with primary hyperoxaluria type 1. Nedosiran, a RNAi therapy targeting lactate dehydrogenase and reducing conversion of glyoxylate to oxalate, is being tested in a phase 3 study (clinicaltrials.gov/ct2/show/NCT04042402). If these emerging therapies are confirmed to be efficient and safe in patients on dialysis and in kidney graft recipients, liver transplantation may perhaps no longer be required in the future.22

Secondary HyperoxaluriaCauses of Secondary Hyperoxaluria

Secondary hyperoxaluria results from (1) increased dietary oxalate or oxalate precursor intake, (2) fat malabsorption, and (3) decreased intestinal oxalate degradation due to alterations in gut microbiota (Fig 1; Box 1). Hyperoxaluria has been associated with increased intake of nuts, tea, Averrhoa carambola (star fruit) and bilimbi, rhubarb, chaga mushroom, spinach, and “green smoothies” and “juicing.”4 Ascorbic acid (vitamin C), ethylene glycol, naftidrofuryl oxalate (a vasodilator), and methoxyflurane (an anesthetic agent) all are precursors of oxalate, and excessive intake or exposure may lead to hyperoxaluria (Fig 3). Fat malabsorption from various causes (pancreatic disorders, Roux-en-Y bypass surgery, short bowel disease, Crohn disease, use of orlistat) leads to steatorrhea, calcium binding by fatty acids in the intestinal lumen, increased intestinal absorption of free oxalate, and higher ileal and colonic permeability to oxalate. Secondary hyperoxaluria may also be multifactorial. For example, cystic fibrosis leads to hyperoxaluria via malabsorption due to exocrine pancreatic insufficiency, defects in oxalate exchangers, and microbiota perturbations associated with frequent antibiotic use.26,27

Figure viewer

Figure 3 Oxalate precursors and metabolic pathways.

Box 1

Causes of Secondary Hyperoxaluria and Oxalate Nephropathy

aData mostly obtained from murine models.

Increased intestinal oxalate absorption

•

Chronic pancreatitis

•

Pancreatectomy

•

Use of orlistat (lipase inhibitor)

•

Roux-en-Y gastric bypass

•

Small bowel resection

•

Crohn’s disease

•

Celiac disease

•

Cystic fibrosis

•

Use of somatostatin analogue

Increased dietary oxalate or precursor intake

•

Rhubarb, Averrhoa carambola (star fruit), Averrhoa bilimbi, tea, nuts, “juicing”

•

Vitamin C, ethylene glycol, methoxyflurane, naftidrofuryl oxalate

Decreased intestinal bacterial oxalate degradation

•

Antibiotic use

Others

•

Obesity, genetic variations in oxalate transporters?a

Obesity and the metabolic syndrome are also associated with calcium oxalate nephrolithiasis.28,29 Obese mice show local and systemic inflammation, which contributes to reduced active transcellular oxalate secretion into the bowel via anion exchanger Slc26a6 and enhanced gastrointestinal paracellular absorption of oxalate.29-31 Obesity-associated cholinergic activity also leads to Slc26a6 inhibition.10 Increased dietary ingestion of oxalate and alterations in intestinal microbiota may further contribute to obesity-associated hyperoxaluria.29,31 Moreover, urinary excretion of oxalate is higher in individuals with diabetes mellitus.3 Plasma levels of glyoxylate and glyoxal (a protein glycation product), potential precursors of oxalate, are higher in diabetic patients, possibly contributing to hyperoxaluria.3

Secondary hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation,16 contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy5 (Fig 1). In contrast to primary forms of the disease, characterized by a high systemic oxalate load, secondary hyperoxaluria only leads to extrarenal deposition of oxalate in very rare cases, such as in severe Crohn disease.14

Secondary Hyperoxaluria and Urolithiasis

Hyperoxaluria is the main risk factor for calcium oxalate urolithiasis.5 Supersaturation of calcium oxalate is 10 times more dependent on a rise in urinary oxalate than on an equimolar rise of urinary calcium concentration.5 Urinary oxalate excretion correlates with the risk of developing a kidney stone event.32 In patients with malabsorption, fluid loss and a low urinary pH and citrate level also contribute to the pathogenesis of urolithiasis.27,32 A meta-analysis of 12 observational studies showed a significantly higher risk of stone formation after Roux-en-Y gastric bypass surgery with a pooled relative risk of 1.79 (95% CI, 1.54-2.10).33 Similarly, a recently published review reported a stone incidence ranging from 2% to 38% in patients with malabsorptive states other than after bariatric surgery.27

The risk of calcium oxalate urolithiasis is also associated with intestinal microbiota composition. Healthy oxalate homeostasis in the gastrointestinal tract involves a collaborative effort between numerous bacterial species. In fecal samples from healthy individuals, metagenomics studies reveal a network of bacterial taxa co-occurring with Oxalobacter formigenes, which are less represented in urinary stone formers.34 This would explain why the absence of O formigenes is not causative of stone disease and why colonization with the bacteria failed to reduce urinary oxalate excretion in interventional studies.35 Similarly, children who are calcium oxalate stone formers have fewer oxalate-degrading and butyrate-forming bacterial taxa in the gut, leading to hyperoxaluria. Butyrate maintains the gut mucosal barrier and regulates intestinal SLC26 oxalate transporters.36

In mice, Slc26a1 gene deletion causes a reduction in intestinal secretion of oxalate, leading to hyperoxalemia and hyperoxaluria.37 Human SLC26A1 mutations may presumably lead to urolithiasis via similar mechanisms.1 Additionally, polymorphisms of SLC26A6 in humans may explain accelerated lithogenesis in distinct populations.16,38

Secondary Hyperoxaluria and Oxalate Nephropathy

Oxalate nephropathy is a severe condition resulting from deposition of calcium oxalate crystals in kidney tissue, which causes tubular-interstitial injury and fibrosis, acute kidney injury (AKI), and/or CKD26,39-41 (Fig 4). Most investigators have used the following diagnostic criteria for oxalate nephropathy: (1) progressive kidney disease, (2) oxalate crystal deposition with tubular injury and interstitial nephritis, and (3) exclusion of other etiologies of kidney disease (aside from vascular and/or diabetes-associated nephropathy). A hyperoxaluria-enabling condition should ideally also be identified26,39-41 (Box 2).

Figure viewer

Figure 4 Oxalate nephropathy, kidney biopsy sample. (A) Intratubular translucent polyhedral or rhomboid crystals (black arrows) on light microscopy (hematoxylin and eosin stain, original magnification, ×20). (B) Crystals shown as birefringent under polarized light (original magnification, ×5). Biopsy also shows acute tubular injury and mild interstitial inflammation.

Box 2

Definition of Oxalate Nephropathy

1.

Progressive kidney disease.

2.

Deposition of calcium oxalate crystals (birefringent on polarized light) within tubular epithelial cells, tubular lumens, and less frequently in the interstitium, associated with tubular injury and interstitial nephritis.

3.

Exclusion of other causes of kidney disease (apart from nonspecific microvascular lesions and/or diabetes-associated glomerular lesions).

4.

Ideally, a hyperoxaluria enabling-condition should be identified.

The preval‎ence of oxalate nephropathy is unknown. We recently reported 22 cases (1%) of oxalate nephropathy out of 2,265 consecutive native kidney biopsies performed during a 9-year period.40 Table 1 shows the clinical characteristics and outcomes of patients with oxalate nephropathy reported in 4 case series and 1 systematic review.26,39-42 Upon presentation, most patients had hypertension, diabetes, and/or a history of CKD. The latter may result from past subclinical deposition of oxalate crystals or represent a predisposing factor because of reduced excretion of oxalate.40

Nasr et al, 2008a,39Cartery et al, 2011a,41Lumlertgul et al, 201826Buysschaert et al, 202040Yang et al, 202042

Table 1

Published Cases Series of Secondary Oxalate Nephropathy

Values for categorical variables are given as n (%) or count; for continuous values as mean. Abbreviations: NA, not available (or too few numbers); OxN, oxalate nephropathy; RAAS, renin-angiotensin-aldosterone system; UPCR, urinary protein-creatinine ratio.

a

Included in the systematic review by Lumlertgul et al.26

b

Patients with unknown causes of oxalate nephropathy and those with short duration of exposure (<30 days) to hyperoxaluria-enabling conditions were excluded.

c

Quantitative data from 57 case reports of oxalate nephropathy not reported in Lumlertgul et al.26

d

Twenty-one of 22 patients with available clinical data.

e

Patients with other causes of CKD such as lupus nephritis were included.

f

Some patients had 2 identified hyperoxaluria-enabling conditions.

g

No systematic gastrointestinal and/or genetic workup reported.

h

Normal value ≤ 45 mg/d.

i

Normal value < 32 mg/g.

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Approximately two-thirds of the patients have malabsorption-associated hyperoxaluria.26,40 We found that chronic pancreatitis and gastric bypass were the most common causes of oxalate nephropathy (48%).40 Of note, Lumlertgul et al26 excluded patients with a short duration of exposure (<30 days) to the hyperoxaluria-enabling conditions (ie, vitamin C and oxalate-rich foods). Interestingly, hyperoxaluria-enabling conditions (ie, malabsorptive states) may be long standing; we reported the development of oxalate nephropathy a mean of 8 years after gastric bypass in 5 patients and 1 and 8 years after orlistat initiation in 2 patients.40 This suggests that the combination of the hyperoxaluria-enabling condition with an additional factor or trigger may lead to crystal formation and kidney damage40,4143,44 (Fig 1). Factors such as acute dehydration, diuretic use, inflammation, antibiotic use, or high dietary oxalate intake may increase the urinary oxalate concentration. Renin-angiotensin-aldosterone system (RAAS) blocker use is also highly preval‎ent in patients presenting with oxalate nephropathy and may favor oxalate crystal-associated kidney injury via the reduction of glomerular filtration fraction.39-41

Clinical presentation of oxalate nephropathy varies across the spectrum of AKI, AKI on CKD, and CKD. Patients present with kidney failure in most cases (mean serum creatinine level of 4.9-8.0 mg/dL). Moderate to profound hypocalcemia was reported in 9 of 12 patients with oxalate nephropathy associated with chronic pancreatitis and may evoke the diagnosis.41 Kidney biopsy shows variable degrees of acute tubular necrosis, interstitial nephritis, and chronic damage. In addition, a substantial proportion of patients have glomerular changes (mostly glomerulosclerosis, associated or not with diabetes). The prognosis of oxalate nephropathy is variable, with approximately half of patients rapidly reaching kidney failure. The outcome may be more favorable in patients presenting with oxalate nephropathy secondary to acute ingestion of high amounts of dietary oxalate.4

Calcium oxalate crystals are most commonly found in proximal and distal tubules in the cortex. They are deposited within tubular lumens, tubular epithelial cells, and less frequently in the interstitium.45 Calcium oxalate crystals are strongly birefringent on polarized light, unlike calcium phosphate crystals46 (Fig 4). Of note, scarce calcium oxalate crystals may be found in tubules in patients with other causes of kidney damage, especially in the setting of reduced eGFR.31,39,41,42 We thus recently suggested adding an oxalate crystal to glomerulus ratio of ≥0.25 in the definition of oxalate nephropathy. Indeed, we found that this ratio separates patients with oxalate nephropathy from those with other well-documented kidney diseases and scarce calcium oxalate crystals.40 Further studies are needed to validate this criterion for distinguishing oxalate nephropathy from nonspecific oxalate deposition. It is also worth noting that although the term “nephrocalcinosis” is often used to refer to calcium salt deposits in kidney tissue, it should probably be used for calcium phosphate and not for calcium oxalate deposition.47

Studies have shown that different crystals such as calcium oxalate, uric acid, and monoclonal light chains share cellular and molecular mechanisms leading to kidney damage, such as stimulation of the NLRP3 inflammasome, a multiprotein oligomer that triggers interleukin-1β (IL-1β)-induced inflammation.48-51 In mice, Nlrp3 deletion successfully protects from progressive kidney failure secondary to ingestion of a diet high in soluble oxalate.51 Nlrp3 inhibition in hyperoxaluric mice protects against calcium oxalate deposition and CKD via a shift in the phenotype of renal macrophages, promoting anti-inflammatory rather than proinflammatory and profibrotic responses. The IL-1 inhibitor anakinra did not show such a protective effect, suggesting that Nlrp3 contributes to calcium oxalate deposition–induced kidney fibrosis independently from IL-1-mediated tissue injury.52

The characteristics of crystal deposition condition the clinical presentation. Acute supersaturation, rapid crystal formation, direct and indirect kidney epithelial cytotoxicity, and inflammation-driven cell necrosis lead to acute kidney damage. By contrast, ongoing mild supersaturation generating subacute crystal plug formation in distal tubules or collecting ducts leads to CKD.48 Crystal deposition is a potent driver of kidney fibrosis, leading to loss of kidney function.48,49

Hyperoxaluria and Progression of CKD

Given the potential nephrotoxicity of oxalate at high levels, Waikar et al53 hypothesized that a higher urinary oxalate, even within the reference range, would be associated with a higher risk of CKD progression. They tested this hypothesis in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective multicenter cohort study of risk factors for cardiovascular disease, progression of CKD, and mortality in patients with mild to moderate CKD. Among 3,123 participants, they showed that higher versus lower 24-hour urinary oxalate excretion (at the 40th percentile) was independently associated with a 32% higher risk of CKD progression and 37% higher risk of kidney failure.53

The association between hyperoxaluria and faster decline in eGFR was also shown in a small cohort of patients with chronic pancreatitis.54 Similarly, previous studies have suggested that calcium oxalate deposition in kidney graft biopsies may be associated with lesser graft function beyond the early posttransplant period.55,56 Urinary oxalate excretion may thus be a potential risk factor for progression in common forms of CKD. Likewise, it has been suggested that urinary oxalate may be a potential mediator of CKD development and progression in individuals with diabetes or obesity.3 Altogether, if these results are confirmed, the question of whether lowering urinary oxalate excretion could be beneficial in slowing CKD progression would need to be addressed.

Management of Secondary Hyperoxaluria and Oxalate Nephropathy

Treatment should be initiated rapidly, starting with high fluid intake16,27,57 (Table 2). The goal is to obtain a daily urine output in excess of 2-3 liters in order to reduce urinary supersaturation with oxalate. Dietary measures to reduce intestinal oxalate absorption include a low-oxalate, low-fat, and normal calcium diet.27 Additionally, calcium supplements are given orally to reduce the bioavailability of intestinal oxalate and its absorption.27,58 Crystallization inhibitors such as citrate may also be used.59 Importantly, all studies performed with these interventions were performed on small numbers of individuals for a limited periods of time, often without control groups or randomization.60

TreatmentRationaleSupporting evidence

High fluid intake (urine output >2-3 L/d)	Reduces urine calcium oxalate supersaturation.	Reduces stone formation.67,68
Low-oxalate diet	Reduces bioavailability of intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies; caveat: comparisons were based on a low-oxalate diet compared to a very-high-oxalate diet.60,69,70
Low-fat diet	Reduces intestinal oxalate absorption (by increasing bioavailability of intestinal calcium).	Reduces urinary oxalate excretion in small studies.70,71
Normal-calcium diet	Avoid low-calcium diets, which lead to more free intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies.69,72
Calcium supplements	Reduce bioavailability of intestinal oxalate and its absorption.	Reduces urinary oxalate excretion but may lead to hypercalciuria.72-74 Calcium citrate may be more bioavailable than calcium carbonate.75
Cholestyramine	Binds intestinal bile acids, reduces diarrhea, and binds oxalate in vitro.	Studies show contradicting results.70,73,76
Oxalobacter formigenes administration	Increases intestinal oxalate degradation.	Reduces urinary oxalate excretion in rat model61,77 and plasma oxalate levels in dialysis patients with primary hyperoxaluria (phase 2 study).35
Oxalate decarboxylase	Degrades intestinal oxalate.	Reduces urinary oxalate excretion in rat model78 and in phase 3 pilot study in humans.62
NLRP3-specific inflammasome inhibitor	Reduces crystal-induced kidney damage.	Reduces calcium-oxalate crystal-induced kidney fibrosis in mouse model.63

Table 2

Current and Potential Therapies of Secondary Hyperoxaluria

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The therapeutic options currently being tested include oral administration of intestinal bacteria and/or enzymes capable of degrading oxalate. O formigenes administration has been shown to reduce urinary oxalate excretion in animal models with enteric hyperoxaluria.61 In humans, this strategy has only been tested in patients with primary hyperoxaluria.35 Oxalate decarboxylase, an oxalate-degrading enzyme, was shown in a pilot phase 3 open-label study to reduce urinary oxalate excretion among 16 patients with both secondary hyperoxaluria and a history of kidney stones.62 The results will need to be confirmed in the phase 3 follow-up randomized controlled trial. A better understanding of the molecular mechanisms of crystal nephropathies may also lead to the development of targeted therapies.48 As previously mentioned, a NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.63

A diagnostic workup is fundamental to treating the underlying cause of hyperoxaluria. Hyperoxaluria-enabling conditions may be long standing but paucisymptomatic. We have shown, for example, that chronic pancreatitis may frequently be diagnosed only after oxalate nephropathy, even in kidney transplant recipients.40,41,64 Morpho-constitutional analysis of kidney stones, combining stereomicroscopy and Fourier-transform infrared spectroscopy, may help in determining the cause of hyperoxaluria.65 Dietary hyperoxaluria may be difficult to identify because oxalate content is not provided by food manufacturers and food tables often report conflicting data on oxalate content.60 In patients with hyperoxaluria and/or oxalate nephropathy of unknown etiology, primary hyperoxaluria must not be overlooked (see the previous section).66

Treatment of the underlying cause of secondary hyperoxaluria includes withdrawal of oxalate-rich foods or precursors, pancreatic enzyme therapy, intensification of Crohn disease therapy, and in some cases reversal of gastric bypass. Identification and management of the cause of secondary hyperoxaluria is also important to minimize the risk of recurrence of oxalate nephropathy after kidney transplantation. Therapeutic considerations concerning patients with secondary hyperoxaluria on dialysis and during the peritransplantation period are beyond the scope of this review. In addition, further studies are needed to determine the clinical significance of hyperoxaluria in asymptomatic patients with hyperoxaluria-enabling conditions in order to determine the subset with the greatest likelihood of deriving benefit from treatment aimed at preventing renal complications.

Conclusions

Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and associated kidney damage. Prompt recognition and management of primary and secondary hyperoxaluria is crucial. Fortunately, novel targeted therapeutic approaches are on the horizon for patients with primary hyperoxaluria.

Article InformationAuthors’ Full Names and Academic Degrees

Nathalie Demoulin, MD, Selda Aydin, MD, PhD, Valentine Gillion, MD, Johann Morelle, MD, PhD, and Michel Jadoul, MD.

Support

None.

Financial Disclosure

The authors declare that they have no relevant financial interests.

Peer Review

Received March 28, 2021. Eval‎uated by 3 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor and a Deputy Editor. Accepted in revised form July 27, 2021.

References

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Sayer, J.A.

Progress in understanding the genetics of calcium-containing nephrolithiasis

J Am Soc Nephrol. 2017; 28:748-759

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ReviewVolume 79, Issue 5p717-727May 2022

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Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review

Nathalie Demoulin1,3 nathalie.demoulin@uclouvain.be ∙ Selda Aydin2,3 ∙ Valentine Gillion1,3 ∙ Johann Morelle1,3 ∙ Michel Jadoul1,3

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Abstract

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.

Index Words

1. Calcium oxalate crystals
2. chronic kidney disease (CKD)
3. crystallopathies
4. fat malabsorption
5. kidney failure
6. lumasiran
7. nephrolithiasis
8. oxalate
9. oxalate nephropathy
10. oxalosis
11. primary hyperoxaluria
12. review
13. secondary hyperoxaluria
14. steatorrhea
15. urolithiasis

Introduction

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, leading to a condition termed oxalate nephropathy. We discuss the progress made in the understanding of intestinal and renal handling of oxalate and crystal-induced kidney damage and review the diagnosis and management of primary and secondary hyperoxaluria.

Oxalate Metabolism and Measurement

Oxalate, the ionized form of oxalic acid, originates from both hepatic production as part of normal metabolism and absorption by the bowel from food (Fig 1). Hepatic synthesis of oxalate from glyoxylate contributes to 60%-80% of plasma oxalate1,2 (Fig 2). Dietary sources rich in oxalate include leafy vegetables, nuts, tea, and fruits rich in vitamin C.3,4 Average daily oxalate intake is approximately 80-130 mg.5,6 Only 5% to 15% of dietary oxalate is normally absorbed because oxalate bound to calcium in the gut is eliminated in the stools and oxalate is degraded by intestinal bacteria, such as Oxalobacter formigenes1,7 (Fig 1).

Figure viewer

Figure 1 Causes and consequences of secondary hyperoxaluria. Secondary hyperoxaluria results from increased dietary oxalate or oxalate precursor intake, fat malabsorption, and decreased intestinal oxalate degradation due to alterations in gut microbiota. Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to nephrolithiasis, oxalate nephropathy, and possibly CKD progression. Based on information in Sayer et al,1 Ermer et al,7 Hoppe et al,5 and Aronson et al.79 Abbreviations: CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system.

Figure viewer

Figure 2 Glyoxylate metabolism in the hepatocyte and enzymatic deficiencies in primary hyperoxaluria. Primary hyperoxaluria types 1 and 2, associated with peroxisomal AGT and cytosolic GRHPR deficiency respectively, result in accumulation of glyoxylate, which is converted to oxalate by LDH. Primary hyperoxaluria 3 is caused by a defect in HOGA in mitochondria; mechanisms leading to increased oxalate levels are not well-defined. GO catalyses the conversion of glycolate to glyoxylate and glyoxylate to oxalate. RNA interference (RNAi)-based drugs targeting GO and LDH are potential therapies for patients with PH1. Abbreviations: AGT, alanine-glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase–hydroxypyruvate reductase; HOGA, 4-hydroxy-2-oxoglutarate aldolase; LDH, lactate dehydrogenase. Based on information in Cochat and Rumsby,23 Hoppe,2 and Devresse et al.22

Oxalate is absorbed in the gut via paracellular passive transport, but there is also strong evidence of active intestinal absorption and secretion via transcellular oxalate anion exchangers of the solute-linked carrier 26 (SCL26) family. The relative contribution of oxalate absorption involving paracellular and transcellular pathways and secretion determines the overall net oxalate movement across the intestine.8 SLC26A1 and SCL26A6 exchangers are expressed in the basolateral and apical membrane of enterocytes, respectively, allowing oxalate secretion into the intestinal lumen. SLC26A3 is an apical oxalate transporter mediating oxalate uptake.1,7 Studies suggest a remarkable adaptive capacity of the intestine to either actively absorb or secrete oxalate in response to local and systemic inputs integrated through the endocrine and autonomic nervous systems.8 Cholinergic regulation inhibits oxalate uptake through reduced expression‎ of SCL26A6 in human cell lines.8-10 A purinergic signaling system also regulates oxalate transport across digestive epithelia.11,12 In murine chronic kidney disease (CKD) models, Slc26a6-mediated enteric oxalate secretion is critical in lowering the body burden of oxalate.13

Plasma oxalate does not have any known function in the human body and is rapidly excreted by the kidney via glomerular filtration and tubular secretion. Both mechanisms are critical in regulating plasma oxalate levels.14,15 SCL26A6 is also located at the apical membrane of the proximal tubule and actively transports oxalate into the urinary filtrate. SLC26A1 is localized to the basolateral membrane of the tubular cell and is thought to reduce urinary oxalate secretion.1,7

Urinary oxalate excretion in healthy adults is influenced by dietary intake, and levels exceeding 40-45 mg/d (500 μmol/d) define hyperoxaluria.16 Oxaluria may also be quantified using the oxalate to creatinine ratio on a spot urine sample.17 Studies have shown a good correlation between spot level and 24-hour excretion, with no significant diurnal pattern of oxalate excretion.18,19 In individuals with stages 4 and 5 CKD, urinary oxalate excretion decreases and plasma oxalate starts to rise.20 Plasma oxalate levels are used to monitor primary hyperoxaluria patients with CKD and on dialysis before transplantation.21,22 Plasma oxalate levels should be <30 μmol/L at the end of each dialysis session because this is the threshold value for oversaturation of plasma calcium oxalate.5

However, accurate measurement of plasma oxalate concentration is challenging. Prompt acidification or freezing of samples and storage at −80°C until acidification is required to prevent conversion of plasma ascorbate to oxalate.20 Moreover, plasma oxalate levels do not correlate well with estimated glomerular filtration rate (eGFR) and show significant intraindividual variation in patients with primary hyperoxaluria.21

Primary Hyperoxaluria

Primary hyperoxaluria types 1, 2, and 3 are rare autosomal recessive inherited disorders of glyoxylate metabolism caused by pathogenic variants in AGXT, GRHPR, or HOGA1, respectively (Fig 2).2,23 The inability to metabolize glyoxylate leads to excessive hepatic production of oxalate and subsequent accumulation in various organs, including the kidney.2,23 Massive urolithiasis and/or calcium oxalate deposition in the renal parenchyma impairs kidney function and oxalate elimination. When the eGFR drops to ≤30-45 mL/min/1.73 m2, plasma oxalate increases, and oxalate may deposit in bone, kidneys, skin, retina, and the cardiovascular and central nervous systems. This dramatic condition is referred to as systemic oxalosis.2,22,23 Primary hyperoxaluria type 1 is the most common and severe form, generally leading to kidney failure during the first 3 decades of life. However, in some patients the condition is not diagnosed until adulthood with occasional or recurrent urolithiasis as the only clinical manifestations. The Gly170Arg and Phe152Ile variants in AGXT (a glycine to arginine substitution at amino acid 170 and a phenylalanine to isoleucine substitution at amino acid 152, respectively) are associated with adult-onset hyperoxaluria and with a less severe prognosis, partly due to the response to pyridoxine.23 Primary hyperoxaluria types 2 and 3 are generally milder, although patients with type 2 may present with CKD caused by recurrent urolithiasis.2,23

Prompt diagnosis of primary hyperoxaluria is essential to prevent downstream complications. Unfortunately, up to 50% of patients have advanced CKD or kidney failure at diagnosis, and approximately 10% are diagnosed after disease recurrence on a kidney allograft.2 As a result, the possibility of primary hyperoxaluria should be systematically considered among children with kidney stones or nephrocalcinosis and in adults with recurrent calcium oxalate stones. Patients with primary hyperoxaluria usually have a higher urinary oxalate excretion (>100 mg/d, >1.0 mmol/1.73 m2/d, or 1,000 μmol/d) than those with secondary hyperoxaluria (50-100 mg/d, 0.5-1.0 mmol/1.73 m2/d, or 500-1,000 μmol/d).2 In children, age-specific reference ranges for spot urinary oxalate to creatinine ratios are used.2,17 Measures of plasma oxalate level may be helpful in patients with CKD stage 3b because they generally increase only when the eGFR is below 30 mL/min/1.73 m2 in patients with CKD from other etiologies. The definitive diagnosis of primary hyperoxaluria is achieved by molecular genetic testing.2,23

The conservative therapeutic options in primary hyperoxaluria include massive fluid intake (tube or gastrostomy feeding in infants), calcium oxalate crystallization inhibitors, and vitamin B6 (pyridoxine) in primary hyperoxaluria type 1.23 To date, liver transplantation is the only established “curative” therapy to correct the metabolic defect contributing to excessive endogenous oxalate formation.2,22,23 Liver-kidney transplantation (simultaneously or sequentially) is the current standard of care in patients with primary hyperoxaluria type 1 and CKD. It should ideally be performed before the development of systemic oxalosis and related complications.22-24 Indeed, outcomes after kidney transplantation are improved by a substantial residual kidney function and by the absence of major systemic oxalate load.23 Oliguria should be avoided in the peritransplant period; in this respect, minimizing the risk of acute tubular necrosis of the graft may impact the choice of donor. In patients with kidney failure awaiting transplantation, intensive hemodialysis strategies limit systemic oxalate accumulation.22,23

New promising therapeutic agents are under investigation and are expected to dramatically influence the management and outcomes of patients with primary hyperoxaluria. Lumasiran is a RNA interference (RNAi)-based therapy that blocks the synthesis of oxalate glycolate oxidase and reduces oxidation of glycolate to glyoxylate, the immediate precursor of oxalate (Fig 2). In the phase 3 ILLUMINATE-A study, patients with primary hyperoxaluria type 1 receiving lumasiran showed a significant reduction in urinary oxalate excretion after 6 months of treatment in comparison with the placebo group.25 Two additional phase 3 trials testing the efficacy and safety of lumasiran are ongoing: ILLUMINATE-B (ClinicalTrials.gov identifier www.clinicaltrials.gov/ct2/show/NCT03905694) and ILLUMINATE-C (clinicaltrials.gov/ct2/show/NCT04152200).22 The US Food and Drug Administration and European Medicines Agency have recently approved lumasiran for the treatment of children and adults with primary hyperoxaluria type 1. Nedosiran, a RNAi therapy targeting lactate dehydrogenase and reducing conversion of glyoxylate to oxalate, is being tested in a phase 3 study (clinicaltrials.gov/ct2/show/NCT04042402). If these emerging therapies are confirmed to be efficient and safe in patients on dialysis and in kidney graft recipients, liver transplantation may perhaps no longer be required in the future.22

Secondary HyperoxaluriaCauses of Secondary Hyperoxaluria

Secondary hyperoxaluria results from (1) increased dietary oxalate or oxalate precursor intake, (2) fat malabsorption, and (3) decreased intestinal oxalate degradation due to alterations in gut microbiota (Fig 1; Box 1). Hyperoxaluria has been associated with increased intake of nuts, tea, Averrhoa carambola (star fruit) and bilimbi, rhubarb, chaga mushroom, spinach, and “green smoothies” and “juicing.”4 Ascorbic acid (vitamin C), ethylene glycol, naftidrofuryl oxalate (a vasodilator), and methoxyflurane (an anesthetic agent) all are precursors of oxalate, and excessive intake or exposure may lead to hyperoxaluria (Fig 3). Fat malabsorption from various causes (pancreatic disorders, Roux-en-Y bypass surgery, short bowel disease, Crohn disease, use of orlistat) leads to steatorrhea, calcium binding by fatty acids in the intestinal lumen, increased intestinal absorption of free oxalate, and higher ileal and colonic permeability to oxalate. Secondary hyperoxaluria may also be multifactorial. For example, cystic fibrosis leads to hyperoxaluria via malabsorption due to exocrine pancreatic insufficiency, defects in oxalate exchangers, and microbiota perturbations associated with frequent antibiotic use.26,27

Figure viewer

Figure 3 Oxalate precursors and metabolic pathways.

Box 1

Causes of Secondary Hyperoxaluria and Oxalate Nephropathy

aData mostly obtained from murine models.

Increased intestinal oxalate absorption

•

Chronic pancreatitis

•

Pancreatectomy

•

Use of orlistat (lipase inhibitor)

•

Roux-en-Y gastric bypass

•

Small bowel resection

•

Crohn’s disease

•

Celiac disease

•

Cystic fibrosis

•

Use of somatostatin analogue

Increased dietary oxalate or precursor intake

•

Rhubarb, Averrhoa carambola (star fruit), Averrhoa bilimbi, tea, nuts, “juicing”

•

Vitamin C, ethylene glycol, methoxyflurane, naftidrofuryl oxalate

Decreased intestinal bacterial oxalate degradation

•

Antibiotic use

Others

•

Obesity, genetic variations in oxalate transporters?a

Obesity and the metabolic syndrome are also associated with calcium oxalate nephrolithiasis.28,29 Obese mice show local and systemic inflammation, which contributes to reduced active transcellular oxalate secretion into the bowel via anion exchanger Slc26a6 and enhanced gastrointestinal paracellular absorption of oxalate.29-31 Obesity-associated cholinergic activity also leads to Slc26a6 inhibition.10 Increased dietary ingestion of oxalate and alterations in intestinal microbiota may further contribute to obesity-associated hyperoxaluria.29,31 Moreover, urinary excretion of oxalate is higher in individuals with diabetes mellitus.3 Plasma levels of glyoxylate and glyoxal (a protein glycation product), potential precursors of oxalate, are higher in diabetic patients, possibly contributing to hyperoxaluria.3

Secondary hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation,16 contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy5 (Fig 1). In contrast to primary forms of the disease, characterized by a high systemic oxalate load, secondary hyperoxaluria only leads to extrarenal deposition of oxalate in very rare cases, such as in severe Crohn disease.14

Secondary Hyperoxaluria and Urolithiasis

Hyperoxaluria is the main risk factor for calcium oxalate urolithiasis.5 Supersaturation of calcium oxalate is 10 times more dependent on a rise in urinary oxalate than on an equimolar rise of urinary calcium concentration.5 Urinary oxalate excretion correlates with the risk of developing a kidney stone event.32 In patients with malabsorption, fluid loss and a low urinary pH and citrate level also contribute to the pathogenesis of urolithiasis.27,32 A meta-analysis of 12 observational studies showed a significantly higher risk of stone formation after Roux-en-Y gastric bypass surgery with a pooled relative risk of 1.79 (95% CI, 1.54-2.10).33 Similarly, a recently published review reported a stone incidence ranging from 2% to 38% in patients with malabsorptive states other than after bariatric surgery.27

The risk of calcium oxalate urolithiasis is also associated with intestinal microbiota composition. Healthy oxalate homeostasis in the gastrointestinal tract involves a collaborative effort between numerous bacterial species. In fecal samples from healthy individuals, metagenomics studies reveal a network of bacterial taxa co-occurring with Oxalobacter formigenes, which are less represented in urinary stone formers.34 This would explain why the absence of O formigenes is not causative of stone disease and why colonization with the bacteria failed to reduce urinary oxalate excretion in interventional studies.35 Similarly, children who are calcium oxalate stone formers have fewer oxalate-degrading and butyrate-forming bacterial taxa in the gut, leading to hyperoxaluria. Butyrate maintains the gut mucosal barrier and regulates intestinal SLC26 oxalate transporters.36

In mice, Slc26a1 gene deletion causes a reduction in intestinal secretion of oxalate, leading to hyperoxalemia and hyperoxaluria.37 Human SLC26A1 mutations may presumably lead to urolithiasis via similar mechanisms.1 Additionally, polymorphisms of SLC26A6 in humans may explain accelerated lithogenesis in distinct populations.16,38

Secondary Hyperoxaluria and Oxalate Nephropathy

Oxalate nephropathy is a severe condition resulting from deposition of calcium oxalate crystals in kidney tissue, which causes tubular-interstitial injury and fibrosis, acute kidney injury (AKI), and/or CKD26,39-41 (Fig 4). Most investigators have used the following diagnostic criteria for oxalate nephropathy: (1) progressive kidney disease, (2) oxalate crystal deposition with tubular injury and interstitial nephritis, and (3) exclusion of other etiologies of kidney disease (aside from vascular and/or diabetes-associated nephropathy). A hyperoxaluria-enabling condition should ideally also be identified26,39-41 (Box 2).

Figure viewer

Figure 4 Oxalate nephropathy, kidney biopsy sample. (A) Intratubular translucent polyhedral or rhomboid crystals (black arrows) on light microscopy (hematoxylin and eosin stain, original magnification, ×20). (B) Crystals shown as birefringent under polarized light (original magnification, ×5). Biopsy also shows acute tubular injury and mild interstitial inflammation.

Box 2

Definition of Oxalate Nephropathy

1.

Progressive kidney disease.

2.

Deposition of calcium oxalate crystals (birefringent on polarized light) within tubular epithelial cells, tubular lumens, and less frequently in the interstitium, associated with tubular injury and interstitial nephritis.

3.

Exclusion of other causes of kidney disease (apart from nonspecific microvascular lesions and/or diabetes-associated glomerular lesions).

4.

Ideally, a hyperoxaluria enabling-condition should be identified.

The preval‎ence of oxalate nephropathy is unknown. We recently reported 22 cases (1%) of oxalate nephropathy out of 2,265 consecutive native kidney biopsies performed during a 9-year period.40 Table 1 shows the clinical characteristics and outcomes of patients with oxalate nephropathy reported in 4 case series and 1 systematic review.26,39-42 Upon presentation, most patients had hypertension, diabetes, and/or a history of CKD. The latter may result from past subclinical deposition of oxalate crystals or represent a predisposing factor because of reduced excretion of oxalate.40

Nasr et al, 2008a,39Cartery et al, 2011a,41Lumlertgul et al, 201826Buysschaert et al, 202040Yang et al, 202042

Table 1

Published Cases Series of Secondary Oxalate Nephropathy

Values for categorical variables are given as n (%) or count; for continuous values as mean. Abbreviations: NA, not available (or too few numbers); OxN, oxalate nephropathy; RAAS, renin-angiotensin-aldosterone system; UPCR, urinary protein-creatinine ratio.

a

Included in the systematic review by Lumlertgul et al.26

b

Patients with unknown causes of oxalate nephropathy and those with short duration of exposure (<30 days) to hyperoxaluria-enabling conditions were excluded.

c

Quantitative data from 57 case reports of oxalate nephropathy not reported in Lumlertgul et al.26

d

Twenty-one of 22 patients with available clinical data.

e

Patients with other causes of CKD such as lupus nephritis were included.

f

Some patients had 2 identified hyperoxaluria-enabling conditions.

g

No systematic gastrointestinal and/or genetic workup reported.

h

Normal value ≤ 45 mg/d.

i

Normal value < 32 mg/g.

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Approximately two-thirds of the patients have malabsorption-associated hyperoxaluria.26,40 We found that chronic pancreatitis and gastric bypass were the most common causes of oxalate nephropathy (48%).40 Of note, Lumlertgul et al26 excluded patients with a short duration of exposure (<30 days) to the hyperoxaluria-enabling conditions (ie, vitamin C and oxalate-rich foods). Interestingly, hyperoxaluria-enabling conditions (ie, malabsorptive states) may be long standing; we reported the development of oxalate nephropathy a mean of 8 years after gastric bypass in 5 patients and 1 and 8 years after orlistat initiation in 2 patients.40 This suggests that the combination of the hyperoxaluria-enabling condition with an additional factor or trigger may lead to crystal formation and kidney damage40,4143,44 (Fig 1). Factors such as acute dehydration, diuretic use, inflammation, antibiotic use, or high dietary oxalate intake may increase the urinary oxalate concentration. Renin-angiotensin-aldosterone system (RAAS) blocker use is also highly preval‎ent in patients presenting with oxalate nephropathy and may favor oxalate crystal-associated kidney injury via the reduction of glomerular filtration fraction.39-41

Clinical presentation of oxalate nephropathy varies across the spectrum of AKI, AKI on CKD, and CKD. Patients present with kidney failure in most cases (mean serum creatinine level of 4.9-8.0 mg/dL). Moderate to profound hypocalcemia was reported in 9 of 12 patients with oxalate nephropathy associated with chronic pancreatitis and may evoke the diagnosis.41 Kidney biopsy shows variable degrees of acute tubular necrosis, interstitial nephritis, and chronic damage. In addition, a substantial proportion of patients have glomerular changes (mostly glomerulosclerosis, associated or not with diabetes). The prognosis of oxalate nephropathy is variable, with approximately half of patients rapidly reaching kidney failure. The outcome may be more favorable in patients presenting with oxalate nephropathy secondary to acute ingestion of high amounts of dietary oxalate.4

Calcium oxalate crystals are most commonly found in proximal and distal tubules in the cortex. They are deposited within tubular lumens, tubular epithelial cells, and less frequently in the interstitium.45 Calcium oxalate crystals are strongly birefringent on polarized light, unlike calcium phosphate crystals46 (Fig 4). Of note, scarce calcium oxalate crystals may be found in tubules in patients with other causes of kidney damage, especially in the setting of reduced eGFR.31,39,41,42 We thus recently suggested adding an oxalate crystal to glomerulus ratio of ≥0.25 in the definition of oxalate nephropathy. Indeed, we found that this ratio separates patients with oxalate nephropathy from those with other well-documented kidney diseases and scarce calcium oxalate crystals.40 Further studies are needed to validate this criterion for distinguishing oxalate nephropathy from nonspecific oxalate deposition. It is also worth noting that although the term “nephrocalcinosis” is often used to refer to calcium salt deposits in kidney tissue, it should probably be used for calcium phosphate and not for calcium oxalate deposition.47

Studies have shown that different crystals such as calcium oxalate, uric acid, and monoclonal light chains share cellular and molecular mechanisms leading to kidney damage, such as stimulation of the NLRP3 inflammasome, a multiprotein oligomer that triggers interleukin-1β (IL-1β)-induced inflammation.48-51 In mice, Nlrp3 deletion successfully protects from progressive kidney failure secondary to ingestion of a diet high in soluble oxalate.51 Nlrp3 inhibition in hyperoxaluric mice protects against calcium oxalate deposition and CKD via a shift in the phenotype of renal macrophages, promoting anti-inflammatory rather than proinflammatory and profibrotic responses. The IL-1 inhibitor anakinra did not show such a protective effect, suggesting that Nlrp3 contributes to calcium oxalate deposition–induced kidney fibrosis independently from IL-1-mediated tissue injury.52

The characteristics of crystal deposition condition the clinical presentation. Acute supersaturation, rapid crystal formation, direct and indirect kidney epithelial cytotoxicity, and inflammation-driven cell necrosis lead to acute kidney damage. By contrast, ongoing mild supersaturation generating subacute crystal plug formation in distal tubules or collecting ducts leads to CKD.48 Crystal deposition is a potent driver of kidney fibrosis, leading to loss of kidney function.48,49

Hyperoxaluria and Progression of CKD

Given the potential nephrotoxicity of oxalate at high levels, Waikar et al53 hypothesized that a higher urinary oxalate, even within the reference range, would be associated with a higher risk of CKD progression. They tested this hypothesis in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective multicenter cohort study of risk factors for cardiovascular disease, progression of CKD, and mortality in patients with mild to moderate CKD. Among 3,123 participants, they showed that higher versus lower 24-hour urinary oxalate excretion (at the 40th percentile) was independently associated with a 32% higher risk of CKD progression and 37% higher risk of kidney failure.53

The association between hyperoxaluria and faster decline in eGFR was also shown in a small cohort of patients with chronic pancreatitis.54 Similarly, previous studies have suggested that calcium oxalate deposition in kidney graft biopsies may be associated with lesser graft function beyond the early posttransplant period.55,56 Urinary oxalate excretion may thus be a potential risk factor for progression in common forms of CKD. Likewise, it has been suggested that urinary oxalate may be a potential mediator of CKD development and progression in individuals with diabetes or obesity.3 Altogether, if these results are confirmed, the question of whether lowering urinary oxalate excretion could be beneficial in slowing CKD progression would need to be addressed.

Management of Secondary Hyperoxaluria and Oxalate Nephropathy

Treatment should be initiated rapidly, starting with high fluid intake16,27,57 (Table 2). The goal is to obtain a daily urine output in excess of 2-3 liters in order to reduce urinary supersaturation with oxalate. Dietary measures to reduce intestinal oxalate absorption include a low-oxalate, low-fat, and normal calcium diet.27 Additionally, calcium supplements are given orally to reduce the bioavailability of intestinal oxalate and its absorption.27,58 Crystallization inhibitors such as citrate may also be used.59 Importantly, all studies performed with these interventions were performed on small numbers of individuals for a limited periods of time, often without control groups or randomization.60

TreatmentRationaleSupporting evidence

High fluid intake (urine output >2-3 L/d)	Reduces urine calcium oxalate supersaturation.	Reduces stone formation.67,68
Low-oxalate diet	Reduces bioavailability of intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies; caveat: comparisons were based on a low-oxalate diet compared to a very-high-oxalate diet.60,69,70
Low-fat diet	Reduces intestinal oxalate absorption (by increasing bioavailability of intestinal calcium).	Reduces urinary oxalate excretion in small studies.70,71
Normal-calcium diet	Avoid low-calcium diets, which lead to more free intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies.69,72
Calcium supplements	Reduce bioavailability of intestinal oxalate and its absorption.	Reduces urinary oxalate excretion but may lead to hypercalciuria.72-74 Calcium citrate may be more bioavailable than calcium carbonate.75
Cholestyramine	Binds intestinal bile acids, reduces diarrhea, and binds oxalate in vitro.	Studies show contradicting results.70,73,76
Oxalobacter formigenes administration	Increases intestinal oxalate degradation.	Reduces urinary oxalate excretion in rat model61,77 and plasma oxalate levels in dialysis patients with primary hyperoxaluria (phase 2 study).35
Oxalate decarboxylase	Degrades intestinal oxalate.	Reduces urinary oxalate excretion in rat model78 and in phase 3 pilot study in humans.62
NLRP3-specific inflammasome inhibitor	Reduces crystal-induced kidney damage.	Reduces calcium-oxalate crystal-induced kidney fibrosis in mouse model.63

Table 2

Current and Potential Therapies of Secondary Hyperoxaluria

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The therapeutic options currently being tested include oral administration of intestinal bacteria and/or enzymes capable of degrading oxalate. O formigenes administration has been shown to reduce urinary oxalate excretion in animal models with enteric hyperoxaluria.61 In humans, this strategy has only been tested in patients with primary hyperoxaluria.35 Oxalate decarboxylase, an oxalate-degrading enzyme, was shown in a pilot phase 3 open-label study to reduce urinary oxalate excretion among 16 patients with both secondary hyperoxaluria and a history of kidney stones.62 The results will need to be confirmed in the phase 3 follow-up randomized controlled trial. A better understanding of the molecular mechanisms of crystal nephropathies may also lead to the development of targeted therapies.48 As previously mentioned, a NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.63

A diagnostic workup is fundamental to treating the underlying cause of hyperoxaluria. Hyperoxaluria-enabling conditions may be long standing but paucisymptomatic. We have shown, for example, that chronic pancreatitis may frequently be diagnosed only after oxalate nephropathy, even in kidney transplant recipients.40,41,64 Morpho-constitutional analysis of kidney stones, combining stereomicroscopy and Fourier-transform infrared spectroscopy, may help in determining the cause of hyperoxaluria.65 Dietary hyperoxaluria may be difficult to identify because oxalate content is not provided by food manufacturers and food tables often report conflicting data on oxalate content.60 In patients with hyperoxaluria and/or oxalate nephropathy of unknown etiology, primary hyperoxaluria must not be overlooked (see the previous section).66

Treatment of the underlying cause of secondary hyperoxaluria includes withdrawal of oxalate-rich foods or precursors, pancreatic enzyme therapy, intensification of Crohn disease therapy, and in some cases reversal of gastric bypass. Identification and management of the cause of secondary hyperoxaluria is also important to minimize the risk of recurrence of oxalate nephropathy after kidney transplantation. Therapeutic considerations concerning patients with secondary hyperoxaluria on dialysis and during the peritransplantation period are beyond the scope of this review. In addition, further studies are needed to determine the clinical significance of hyperoxaluria in asymptomatic patients with hyperoxaluria-enabling conditions in order to determine the subset with the greatest likelihood of deriving benefit from treatment aimed at preventing renal complications.

Conclusions

Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and associated kidney damage. Prompt recognition and management of primary and secondary hyperoxaluria is crucial. Fortunately, novel targeted therapeutic approaches are on the horizon for patients with primary hyperoxaluria.

Article InformationAuthors’ Full Names and Academic Degrees

Nathalie Demoulin, MD, Selda Aydin, MD, PhD, Valentine Gillion, MD, Johann Morelle, MD, PhD, and Michel Jadoul, MD.

Support

None.

Financial Disclosure

The authors declare that they have no relevant financial interests.

Peer Review

Received March 28, 2021. Eval‎uated by 3 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor and a Deputy Editor. Accepted in revised form July 27, 2021.

References

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Sayer, J.A.

Progress in understanding the genetics of calcium-containing nephrolithiasis

J Am Soc Nephrol. 2017; 28:748-759

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ReviewVolume 79, Issue 5p717-727May 2022

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Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review

Nathalie Demoulin1,3 nathalie.demoulin@uclouvain.be ∙ Selda Aydin2,3 ∙ Valentine Gillion1,3 ∙ Johann Morelle1,3 ∙ Michel Jadoul1,3

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Abstract

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.

Index Words

1. Calcium oxalate crystals
2. chronic kidney disease (CKD)
3. crystallopathies
4. fat malabsorption
5. kidney failure
6. lumasiran
7. nephrolithiasis
8. oxalate
9. oxalate nephropathy
10. oxalosis
11. primary hyperoxaluria
12. review
13. secondary hyperoxaluria
14. steatorrhea
15. urolithiasis

Introduction

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, leading to a condition termed oxalate nephropathy. We discuss the progress made in the understanding of intestinal and renal handling of oxalate and crystal-induced kidney damage and review the diagnosis and management of primary and secondary hyperoxaluria.

Oxalate Metabolism and Measurement

Oxalate, the ionized form of oxalic acid, originates from both hepatic production as part of normal metabolism and absorption by the bowel from food (Fig 1). Hepatic synthesis of oxalate from glyoxylate contributes to 60%-80% of plasma oxalate1,2 (Fig 2). Dietary sources rich in oxalate include leafy vegetables, nuts, tea, and fruits rich in vitamin C.3,4 Average daily oxalate intake is approximately 80-130 mg.5,6 Only 5% to 15% of dietary oxalate is normally absorbed because oxalate bound to calcium in the gut is eliminated in the stools and oxalate is degraded by intestinal bacteria, such as Oxalobacter formigenes1,7 (Fig 1).

Figure viewer

Figure 1 Causes and consequences of secondary hyperoxaluria. Secondary hyperoxaluria results from increased dietary oxalate or oxalate precursor intake, fat malabsorption, and decreased intestinal oxalate degradation due to alterations in gut microbiota. Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to nephrolithiasis, oxalate nephropathy, and possibly CKD progression. Based on information in Sayer et al,1 Ermer et al,7 Hoppe et al,5 and Aronson et al.79 Abbreviations: CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system.

Figure viewer

Figure 2 Glyoxylate metabolism in the hepatocyte and enzymatic deficiencies in primary hyperoxaluria. Primary hyperoxaluria types 1 and 2, associated with peroxisomal AGT and cytosolic GRHPR deficiency respectively, result in accumulation of glyoxylate, which is converted to oxalate by LDH. Primary hyperoxaluria 3 is caused by a defect in HOGA in mitochondria; mechanisms leading to increased oxalate levels are not well-defined. GO catalyses the conversion of glycolate to glyoxylate and glyoxylate to oxalate. RNA interference (RNAi)-based drugs targeting GO and LDH are potential therapies for patients with PH1. Abbreviations: AGT, alanine-glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase–hydroxypyruvate reductase; HOGA, 4-hydroxy-2-oxoglutarate aldolase; LDH, lactate dehydrogenase. Based on information in Cochat and Rumsby,23 Hoppe,2 and Devresse et al.22

Oxalate is absorbed in the gut via paracellular passive transport, but there is also strong evidence of active intestinal absorption and secretion via transcellular oxalate anion exchangers of the solute-linked carrier 26 (SCL26) family. The relative contribution of oxalate absorption involving paracellular and transcellular pathways and secretion determines the overall net oxalate movement across the intestine.8 SLC26A1 and SCL26A6 exchangers are expressed in the basolateral and apical membrane of enterocytes, respectively, allowing oxalate secretion into the intestinal lumen. SLC26A3 is an apical oxalate transporter mediating oxalate uptake.1,7 Studies suggest a remarkable adaptive capacity of the intestine to either actively absorb or secrete oxalate in response to local and systemic inputs integrated through the endocrine and autonomic nervous systems.8 Cholinergic regulation inhibits oxalate uptake through reduced expression‎ of SCL26A6 in human cell lines.8-10 A purinergic signaling system also regulates oxalate transport across digestive epithelia.11,12 In murine chronic kidney disease (CKD) models, Slc26a6-mediated enteric oxalate secretion is critical in lowering the body burden of oxalate.13

Plasma oxalate does not have any known function in the human body and is rapidly excreted by the kidney via glomerular filtration and tubular secretion. Both mechanisms are critical in regulating plasma oxalate levels.14,15 SCL26A6 is also located at the apical membrane of the proximal tubule and actively transports oxalate into the urinary filtrate. SLC26A1 is localized to the basolateral membrane of the tubular cell and is thought to reduce urinary oxalate secretion.1,7

Urinary oxalate excretion in healthy adults is influenced by dietary intake, and levels exceeding 40-45 mg/d (500 μmol/d) define hyperoxaluria.16 Oxaluria may also be quantified using the oxalate to creatinine ratio on a spot urine sample.17 Studies have shown a good correlation between spot level and 24-hour excretion, with no significant diurnal pattern of oxalate excretion.18,19 In individuals with stages 4 and 5 CKD, urinary oxalate excretion decreases and plasma oxalate starts to rise.20 Plasma oxalate levels are used to monitor primary hyperoxaluria patients with CKD and on dialysis before transplantation.21,22 Plasma oxalate levels should be <30 μmol/L at the end of each dialysis session because this is the threshold value for oversaturation of plasma calcium oxalate.5

However, accurate measurement of plasma oxalate concentration is challenging. Prompt acidification or freezing of samples and storage at −80°C until acidification is required to prevent conversion of plasma ascorbate to oxalate.20 Moreover, plasma oxalate levels do not correlate well with estimated glomerular filtration rate (eGFR) and show significant intraindividual variation in patients with primary hyperoxaluria.21

Primary Hyperoxaluria

Primary hyperoxaluria types 1, 2, and 3 are rare autosomal recessive inherited disorders of glyoxylate metabolism caused by pathogenic variants in AGXT, GRHPR, or HOGA1, respectively (Fig 2).2,23 The inability to metabolize glyoxylate leads to excessive hepatic production of oxalate and subsequent accumulation in various organs, including the kidney.2,23 Massive urolithiasis and/or calcium oxalate deposition in the renal parenchyma impairs kidney function and oxalate elimination. When the eGFR drops to ≤30-45 mL/min/1.73 m2, plasma oxalate increases, and oxalate may deposit in bone, kidneys, skin, retina, and the cardiovascular and central nervous systems. This dramatic condition is referred to as systemic oxalosis.2,22,23 Primary hyperoxaluria type 1 is the most common and severe form, generally leading to kidney failure during the first 3 decades of life. However, in some patients the condition is not diagnosed until adulthood with occasional or recurrent urolithiasis as the only clinical manifestations. The Gly170Arg and Phe152Ile variants in AGXT (a glycine to arginine substitution at amino acid 170 and a phenylalanine to isoleucine substitution at amino acid 152, respectively) are associated with adult-onset hyperoxaluria and with a less severe prognosis, partly due to the response to pyridoxine.23 Primary hyperoxaluria types 2 and 3 are generally milder, although patients with type 2 may present with CKD caused by recurrent urolithiasis.2,23

Prompt diagnosis of primary hyperoxaluria is essential to prevent downstream complications. Unfortunately, up to 50% of patients have advanced CKD or kidney failure at diagnosis, and approximately 10% are diagnosed after disease recurrence on a kidney allograft.2 As a result, the possibility of primary hyperoxaluria should be systematically considered among children with kidney stones or nephrocalcinosis and in adults with recurrent calcium oxalate stones. Patients with primary hyperoxaluria usually have a higher urinary oxalate excretion (>100 mg/d, >1.0 mmol/1.73 m2/d, or 1,000 μmol/d) than those with secondary hyperoxaluria (50-100 mg/d, 0.5-1.0 mmol/1.73 m2/d, or 500-1,000 μmol/d).2 In children, age-specific reference ranges for spot urinary oxalate to creatinine ratios are used.2,17 Measures of plasma oxalate level may be helpful in patients with CKD stage 3b because they generally increase only when the eGFR is below 30 mL/min/1.73 m2 in patients with CKD from other etiologies. The definitive diagnosis of primary hyperoxaluria is achieved by molecular genetic testing.2,23

The conservative therapeutic options in primary hyperoxaluria include massive fluid intake (tube or gastrostomy feeding in infants), calcium oxalate crystallization inhibitors, and vitamin B6 (pyridoxine) in primary hyperoxaluria type 1.23 To date, liver transplantation is the only established “curative” therapy to correct the metabolic defect contributing to excessive endogenous oxalate formation.2,22,23 Liver-kidney transplantation (simultaneously or sequentially) is the current standard of care in patients with primary hyperoxaluria type 1 and CKD. It should ideally be performed before the development of systemic oxalosis and related complications.22-24 Indeed, outcomes after kidney transplantation are improved by a substantial residual kidney function and by the absence of major systemic oxalate load.23 Oliguria should be avoided in the peritransplant period; in this respect, minimizing the risk of acute tubular necrosis of the graft may impact the choice of donor. In patients with kidney failure awaiting transplantation, intensive hemodialysis strategies limit systemic oxalate accumulation.22,23

New promising therapeutic agents are under investigation and are expected to dramatically influence the management and outcomes of patients with primary hyperoxaluria. Lumasiran is a RNA interference (RNAi)-based therapy that blocks the synthesis of oxalate glycolate oxidase and reduces oxidation of glycolate to glyoxylate, the immediate precursor of oxalate (Fig 2). In the phase 3 ILLUMINATE-A study, patients with primary hyperoxaluria type 1 receiving lumasiran showed a significant reduction in urinary oxalate excretion after 6 months of treatment in comparison with the placebo group.25 Two additional phase 3 trials testing the efficacy and safety of lumasiran are ongoing: ILLUMINATE-B (ClinicalTrials.gov identifier www.clinicaltrials.gov/ct2/show/NCT03905694) and ILLUMINATE-C (clinicaltrials.gov/ct2/show/NCT04152200).22 The US Food and Drug Administration and European Medicines Agency have recently approved lumasiran for the treatment of children and adults with primary hyperoxaluria type 1. Nedosiran, a RNAi therapy targeting lactate dehydrogenase and reducing conversion of glyoxylate to oxalate, is being tested in a phase 3 study (clinicaltrials.gov/ct2/show/NCT04042402). If these emerging therapies are confirmed to be efficient and safe in patients on dialysis and in kidney graft recipients, liver transplantation may perhaps no longer be required in the future.22

Secondary HyperoxaluriaCauses of Secondary Hyperoxaluria

Secondary hyperoxaluria results from (1) increased dietary oxalate or oxalate precursor intake, (2) fat malabsorption, and (3) decreased intestinal oxalate degradation due to alterations in gut microbiota (Fig 1; Box 1). Hyperoxaluria has been associated with increased intake of nuts, tea, Averrhoa carambola (star fruit) and bilimbi, rhubarb, chaga mushroom, spinach, and “green smoothies” and “juicing.”4 Ascorbic acid (vitamin C), ethylene glycol, naftidrofuryl oxalate (a vasodilator), and methoxyflurane (an anesthetic agent) all are precursors of oxalate, and excessive intake or exposure may lead to hyperoxaluria (Fig 3). Fat malabsorption from various causes (pancreatic disorders, Roux-en-Y bypass surgery, short bowel disease, Crohn disease, use of orlistat) leads to steatorrhea, calcium binding by fatty acids in the intestinal lumen, increased intestinal absorption of free oxalate, and higher ileal and colonic permeability to oxalate. Secondary hyperoxaluria may also be multifactorial. For example, cystic fibrosis leads to hyperoxaluria via malabsorption due to exocrine pancreatic insufficiency, defects in oxalate exchangers, and microbiota perturbations associated with frequent antibiotic use.26,27

Figure viewer

Figure 3 Oxalate precursors and metabolic pathways.

Box 1

Causes of Secondary Hyperoxaluria and Oxalate Nephropathy

aData mostly obtained from murine models.

Increased intestinal oxalate absorption

•

Chronic pancreatitis

•

Pancreatectomy

•

Use of orlistat (lipase inhibitor)

•

Roux-en-Y gastric bypass

•

Small bowel resection

•

Crohn’s disease

•

Celiac disease

•

Cystic fibrosis

•

Use of somatostatin analogue

Increased dietary oxalate or precursor intake

•

Rhubarb, Averrhoa carambola (star fruit), Averrhoa bilimbi, tea, nuts, “juicing”

•

Vitamin C, ethylene glycol, methoxyflurane, naftidrofuryl oxalate

Decreased intestinal bacterial oxalate degradation

•

Antibiotic use

Others

•

Obesity, genetic variations in oxalate transporters?a

Obesity and the metabolic syndrome are also associated with calcium oxalate nephrolithiasis.28,29 Obese mice show local and systemic inflammation, which contributes to reduced active transcellular oxalate secretion into the bowel via anion exchanger Slc26a6 and enhanced gastrointestinal paracellular absorption of oxalate.29-31 Obesity-associated cholinergic activity also leads to Slc26a6 inhibition.10 Increased dietary ingestion of oxalate and alterations in intestinal microbiota may further contribute to obesity-associated hyperoxaluria.29,31 Moreover, urinary excretion of oxalate is higher in individuals with diabetes mellitus.3 Plasma levels of glyoxylate and glyoxal (a protein glycation product), potential precursors of oxalate, are higher in diabetic patients, possibly contributing to hyperoxaluria.3

Secondary hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation,16 contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy5 (Fig 1). In contrast to primary forms of the disease, characterized by a high systemic oxalate load, secondary hyperoxaluria only leads to extrarenal deposition of oxalate in very rare cases, such as in severe Crohn disease.14

Secondary Hyperoxaluria and Urolithiasis

Hyperoxaluria is the main risk factor for calcium oxalate urolithiasis.5 Supersaturation of calcium oxalate is 10 times more dependent on a rise in urinary oxalate than on an equimolar rise of urinary calcium concentration.5 Urinary oxalate excretion correlates with the risk of developing a kidney stone event.32 In patients with malabsorption, fluid loss and a low urinary pH and citrate level also contribute to the pathogenesis of urolithiasis.27,32 A meta-analysis of 12 observational studies showed a significantly higher risk of stone formation after Roux-en-Y gastric bypass surgery with a pooled relative risk of 1.79 (95% CI, 1.54-2.10).33 Similarly, a recently published review reported a stone incidence ranging from 2% to 38% in patients with malabsorptive states other than after bariatric surgery.27

The risk of calcium oxalate urolithiasis is also associated with intestinal microbiota composition. Healthy oxalate homeostasis in the gastrointestinal tract involves a collaborative effort between numerous bacterial species. In fecal samples from healthy individuals, metagenomics studies reveal a network of bacterial taxa co-occurring with Oxalobacter formigenes, which are less represented in urinary stone formers.34 This would explain why the absence of O formigenes is not causative of stone disease and why colonization with the bacteria failed to reduce urinary oxalate excretion in interventional studies.35 Similarly, children who are calcium oxalate stone formers have fewer oxalate-degrading and butyrate-forming bacterial taxa in the gut, leading to hyperoxaluria. Butyrate maintains the gut mucosal barrier and regulates intestinal SLC26 oxalate transporters.36

In mice, Slc26a1 gene deletion causes a reduction in intestinal secretion of oxalate, leading to hyperoxalemia and hyperoxaluria.37 Human SLC26A1 mutations may presumably lead to urolithiasis via similar mechanisms.1 Additionally, polymorphisms of SLC26A6 in humans may explain accelerated lithogenesis in distinct populations.16,38

Secondary Hyperoxaluria and Oxalate Nephropathy

Oxalate nephropathy is a severe condition resulting from deposition of calcium oxalate crystals in kidney tissue, which causes tubular-interstitial injury and fibrosis, acute kidney injury (AKI), and/or CKD26,39-41 (Fig 4). Most investigators have used the following diagnostic criteria for oxalate nephropathy: (1) progressive kidney disease, (2) oxalate crystal deposition with tubular injury and interstitial nephritis, and (3) exclusion of other etiologies of kidney disease (aside from vascular and/or diabetes-associated nephropathy). A hyperoxaluria-enabling condition should ideally also be identified26,39-41 (Box 2).

Figure viewer

Figure 4 Oxalate nephropathy, kidney biopsy sample. (A) Intratubular translucent polyhedral or rhomboid crystals (black arrows) on light microscopy (hematoxylin and eosin stain, original magnification, ×20). (B) Crystals shown as birefringent under polarized light (original magnification, ×5). Biopsy also shows acute tubular injury and mild interstitial inflammation.

Box 2

Definition of Oxalate Nephropathy

1.

Progressive kidney disease.

2.

Deposition of calcium oxalate crystals (birefringent on polarized light) within tubular epithelial cells, tubular lumens, and less frequently in the interstitium, associated with tubular injury and interstitial nephritis.

3.

Exclusion of other causes of kidney disease (apart from nonspecific microvascular lesions and/or diabetes-associated glomerular lesions).

4.

Ideally, a hyperoxaluria enabling-condition should be identified.

The preval‎ence of oxalate nephropathy is unknown. We recently reported 22 cases (1%) of oxalate nephropathy out of 2,265 consecutive native kidney biopsies performed during a 9-year period.40 Table 1 shows the clinical characteristics and outcomes of patients with oxalate nephropathy reported in 4 case series and 1 systematic review.26,39-42 Upon presentation, most patients had hypertension, diabetes, and/or a history of CKD. The latter may result from past subclinical deposition of oxalate crystals or represent a predisposing factor because of reduced excretion of oxalate.40

Nasr et al, 2008a,39Cartery et al, 2011a,41Lumlertgul et al, 201826Buysschaert et al, 202040Yang et al, 202042

Table 1

Published Cases Series of Secondary Oxalate Nephropathy

Values for categorical variables are given as n (%) or count; for continuous values as mean. Abbreviations: NA, not available (or too few numbers); OxN, oxalate nephropathy; RAAS, renin-angiotensin-aldosterone system; UPCR, urinary protein-creatinine ratio.

a

Included in the systematic review by Lumlertgul et al.26

b

Patients with unknown causes of oxalate nephropathy and those with short duration of exposure (<30 days) to hyperoxaluria-enabling conditions were excluded.

c

Quantitative data from 57 case reports of oxalate nephropathy not reported in Lumlertgul et al.26

d

Twenty-one of 22 patients with available clinical data.

e

Patients with other causes of CKD such as lupus nephritis were included.

f

Some patients had 2 identified hyperoxaluria-enabling conditions.

g

No systematic gastrointestinal and/or genetic workup reported.

h

Normal value ≤ 45 mg/d.

i

Normal value < 32 mg/g.

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Approximately two-thirds of the patients have malabsorption-associated hyperoxaluria.26,40 We found that chronic pancreatitis and gastric bypass were the most common causes of oxalate nephropathy (48%).40 Of note, Lumlertgul et al26 excluded patients with a short duration of exposure (<30 days) to the hyperoxaluria-enabling conditions (ie, vitamin C and oxalate-rich foods). Interestingly, hyperoxaluria-enabling conditions (ie, malabsorptive states) may be long standing; we reported the development of oxalate nephropathy a mean of 8 years after gastric bypass in 5 patients and 1 and 8 years after orlistat initiation in 2 patients.40 This suggests that the combination of the hyperoxaluria-enabling condition with an additional factor or trigger may lead to crystal formation and kidney damage40,4143,44 (Fig 1). Factors such as acute dehydration, diuretic use, inflammation, antibiotic use, or high dietary oxalate intake may increase the urinary oxalate concentration. Renin-angiotensin-aldosterone system (RAAS) blocker use is also highly preval‎ent in patients presenting with oxalate nephropathy and may favor oxalate crystal-associated kidney injury via the reduction of glomerular filtration fraction.39-41

Clinical presentation of oxalate nephropathy varies across the spectrum of AKI, AKI on CKD, and CKD. Patients present with kidney failure in most cases (mean serum creatinine level of 4.9-8.0 mg/dL). Moderate to profound hypocalcemia was reported in 9 of 12 patients with oxalate nephropathy associated with chronic pancreatitis and may evoke the diagnosis.41 Kidney biopsy shows variable degrees of acute tubular necrosis, interstitial nephritis, and chronic damage. In addition, a substantial proportion of patients have glomerular changes (mostly glomerulosclerosis, associated or not with diabetes). The prognosis of oxalate nephropathy is variable, with approximately half of patients rapidly reaching kidney failure. The outcome may be more favorable in patients presenting with oxalate nephropathy secondary to acute ingestion of high amounts of dietary oxalate.4

Calcium oxalate crystals are most commonly found in proximal and distal tubules in the cortex. They are deposited within tubular lumens, tubular epithelial cells, and less frequently in the interstitium.45 Calcium oxalate crystals are strongly birefringent on polarized light, unlike calcium phosphate crystals46 (Fig 4). Of note, scarce calcium oxalate crystals may be found in tubules in patients with other causes of kidney damage, especially in the setting of reduced eGFR.31,39,41,42 We thus recently suggested adding an oxalate crystal to glomerulus ratio of ≥0.25 in the definition of oxalate nephropathy. Indeed, we found that this ratio separates patients with oxalate nephropathy from those with other well-documented kidney diseases and scarce calcium oxalate crystals.40 Further studies are needed to validate this criterion for distinguishing oxalate nephropathy from nonspecific oxalate deposition. It is also worth noting that although the term “nephrocalcinosis” is often used to refer to calcium salt deposits in kidney tissue, it should probably be used for calcium phosphate and not for calcium oxalate deposition.47

Studies have shown that different crystals such as calcium oxalate, uric acid, and monoclonal light chains share cellular and molecular mechanisms leading to kidney damage, such as stimulation of the NLRP3 inflammasome, a multiprotein oligomer that triggers interleukin-1β (IL-1β)-induced inflammation.48-51 In mice, Nlrp3 deletion successfully protects from progressive kidney failure secondary to ingestion of a diet high in soluble oxalate.51 Nlrp3 inhibition in hyperoxaluric mice protects against calcium oxalate deposition and CKD via a shift in the phenotype of renal macrophages, promoting anti-inflammatory rather than proinflammatory and profibrotic responses. The IL-1 inhibitor anakinra did not show such a protective effect, suggesting that Nlrp3 contributes to calcium oxalate deposition–induced kidney fibrosis independently from IL-1-mediated tissue injury.52

The characteristics of crystal deposition condition the clinical presentation. Acute supersaturation, rapid crystal formation, direct and indirect kidney epithelial cytotoxicity, and inflammation-driven cell necrosis lead to acute kidney damage. By contrast, ongoing mild supersaturation generating subacute crystal plug formation in distal tubules or collecting ducts leads to CKD.48 Crystal deposition is a potent driver of kidney fibrosis, leading to loss of kidney function.48,49

Hyperoxaluria and Progression of CKD

Given the potential nephrotoxicity of oxalate at high levels, Waikar et al53 hypothesized that a higher urinary oxalate, even within the reference range, would be associated with a higher risk of CKD progression. They tested this hypothesis in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective multicenter cohort study of risk factors for cardiovascular disease, progression of CKD, and mortality in patients with mild to moderate CKD. Among 3,123 participants, they showed that higher versus lower 24-hour urinary oxalate excretion (at the 40th percentile) was independently associated with a 32% higher risk of CKD progression and 37% higher risk of kidney failure.53

The association between hyperoxaluria and faster decline in eGFR was also shown in a small cohort of patients with chronic pancreatitis.54 Similarly, previous studies have suggested that calcium oxalate deposition in kidney graft biopsies may be associated with lesser graft function beyond the early posttransplant period.55,56 Urinary oxalate excretion may thus be a potential risk factor for progression in common forms of CKD. Likewise, it has been suggested that urinary oxalate may be a potential mediator of CKD development and progression in individuals with diabetes or obesity.3 Altogether, if these results are confirmed, the question of whether lowering urinary oxalate excretion could be beneficial in slowing CKD progression would need to be addressed.

Management of Secondary Hyperoxaluria and Oxalate Nephropathy

Treatment should be initiated rapidly, starting with high fluid intake16,27,57 (Table 2). The goal is to obtain a daily urine output in excess of 2-3 liters in order to reduce urinary supersaturation with oxalate. Dietary measures to reduce intestinal oxalate absorption include a low-oxalate, low-fat, and normal calcium diet.27 Additionally, calcium supplements are given orally to reduce the bioavailability of intestinal oxalate and its absorption.27,58 Crystallization inhibitors such as citrate may also be used.59 Importantly, all studies performed with these interventions were performed on small numbers of individuals for a limited periods of time, often without control groups or randomization.60

TreatmentRationaleSupporting evidence

High fluid intake (urine output >2-3 L/d)	Reduces urine calcium oxalate supersaturation.	Reduces stone formation.67,68
Low-oxalate diet	Reduces bioavailability of intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies; caveat: comparisons were based on a low-oxalate diet compared to a very-high-oxalate diet.60,69,70
Low-fat diet	Reduces intestinal oxalate absorption (by increasing bioavailability of intestinal calcium).	Reduces urinary oxalate excretion in small studies.70,71
Normal-calcium diet	Avoid low-calcium diets, which lead to more free intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies.69,72
Calcium supplements	Reduce bioavailability of intestinal oxalate and its absorption.	Reduces urinary oxalate excretion but may lead to hypercalciuria.72-74 Calcium citrate may be more bioavailable than calcium carbonate.75
Cholestyramine	Binds intestinal bile acids, reduces diarrhea, and binds oxalate in vitro.	Studies show contradicting results.70,73,76
Oxalobacter formigenes administration	Increases intestinal oxalate degradation.	Reduces urinary oxalate excretion in rat model61,77 and plasma oxalate levels in dialysis patients with primary hyperoxaluria (phase 2 study).35
Oxalate decarboxylase	Degrades intestinal oxalate.	Reduces urinary oxalate excretion in rat model78 and in phase 3 pilot study in humans.62
NLRP3-specific inflammasome inhibitor	Reduces crystal-induced kidney damage.	Reduces calcium-oxalate crystal-induced kidney fibrosis in mouse model.63

Table 2

Current and Potential Therapies of Secondary Hyperoxaluria

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The therapeutic options currently being tested include oral administration of intestinal bacteria and/or enzymes capable of degrading oxalate. O formigenes administration has been shown to reduce urinary oxalate excretion in animal models with enteric hyperoxaluria.61 In humans, this strategy has only been tested in patients with primary hyperoxaluria.35 Oxalate decarboxylase, an oxalate-degrading enzyme, was shown in a pilot phase 3 open-label study to reduce urinary oxalate excretion among 16 patients with both secondary hyperoxaluria and a history of kidney stones.62 The results will need to be confirmed in the phase 3 follow-up randomized controlled trial. A better understanding of the molecular mechanisms of crystal nephropathies may also lead to the development of targeted therapies.48 As previously mentioned, a NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.63

A diagnostic workup is fundamental to treating the underlying cause of hyperoxaluria. Hyperoxaluria-enabling conditions may be long standing but paucisymptomatic. We have shown, for example, that chronic pancreatitis may frequently be diagnosed only after oxalate nephropathy, even in kidney transplant recipients.40,41,64 Morpho-constitutional analysis of kidney stones, combining stereomicroscopy and Fourier-transform infrared spectroscopy, may help in determining the cause of hyperoxaluria.65 Dietary hyperoxaluria may be difficult to identify because oxalate content is not provided by food manufacturers and food tables often report conflicting data on oxalate content.60 In patients with hyperoxaluria and/or oxalate nephropathy of unknown etiology, primary hyperoxaluria must not be overlooked (see the previous section).66

Treatment of the underlying cause of secondary hyperoxaluria includes withdrawal of oxalate-rich foods or precursors, pancreatic enzyme therapy, intensification of Crohn disease therapy, and in some cases reversal of gastric bypass. Identification and management of the cause of secondary hyperoxaluria is also important to minimize the risk of recurrence of oxalate nephropathy after kidney transplantation. Therapeutic considerations concerning patients with secondary hyperoxaluria on dialysis and during the peritransplantation period are beyond the scope of this review. In addition, further studies are needed to determine the clinical significance of hyperoxaluria in asymptomatic patients with hyperoxaluria-enabling conditions in order to determine the subset with the greatest likelihood of deriving benefit from treatment aimed at preventing renal complications.

Conclusions

Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and associated kidney damage. Prompt recognition and management of primary and secondary hyperoxaluria is crucial. Fortunately, novel targeted therapeutic approaches are on the horizon for patients with primary hyperoxaluria.

Article InformationAuthors’ Full Names and Academic Degrees

Nathalie Demoulin, MD, Selda Aydin, MD, PhD, Valentine Gillion, MD, Johann Morelle, MD, PhD, and Michel Jadoul, MD.

Support

None.

Financial Disclosure

The authors declare that they have no relevant financial interests.

Peer Review

Received March 28, 2021. Eval‎uated by 3 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor and a Deputy Editor. Accepted in revised form July 27, 2021.

References

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Sayer, J.A.

Progress in understanding the genetics of calcium-containing nephrolithiasis

J Am Soc Nephrol. 2017; 28:748-759

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ReviewVolume 79, Issue 5p717-727May 2022

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Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review

Nathalie Demoulin1,3 nathalie.demoulin@uclouvain.be ∙ Selda Aydin2,3 ∙ Valentine Gillion1,3 ∙ Johann Morelle1,3 ∙ Michel Jadoul1,3

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Abstract

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.

Index Words

1. Calcium oxalate crystals
2. chronic kidney disease (CKD)
3. crystallopathies
4. fat malabsorption
5. kidney failure
6. lumasiran
7. nephrolithiasis
8. oxalate
9. oxalate nephropathy
10. oxalosis
11. primary hyperoxaluria
12. review
13. secondary hyperoxaluria
14. steatorrhea
15. urolithiasis

Introduction

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, leading to a condition termed oxalate nephropathy. We discuss the progress made in the understanding of intestinal and renal handling of oxalate and crystal-induced kidney damage and review the diagnosis and management of primary and secondary hyperoxaluria.

Oxalate Metabolism and Measurement

Oxalate, the ionized form of oxalic acid, originates from both hepatic production as part of normal metabolism and absorption by the bowel from food (Fig 1). Hepatic synthesis of oxalate from glyoxylate contributes to 60%-80% of plasma oxalate1,2 (Fig 2). Dietary sources rich in oxalate include leafy vegetables, nuts, tea, and fruits rich in vitamin C.3,4 Average daily oxalate intake is approximately 80-130 mg.5,6 Only 5% to 15% of dietary oxalate is normally absorbed because oxalate bound to calcium in the gut is eliminated in the stools and oxalate is degraded by intestinal bacteria, such as Oxalobacter formigenes1,7 (Fig 1).

Figure viewer

Figure 1 Causes and consequences of secondary hyperoxaluria. Secondary hyperoxaluria results from increased dietary oxalate or oxalate precursor intake, fat malabsorption, and decreased intestinal oxalate degradation due to alterations in gut microbiota. Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, contributing to nephrolithiasis, oxalate nephropathy, and possibly CKD progression. Based on information in Sayer et al,1 Ermer et al,7 Hoppe et al,5 and Aronson et al.79 Abbreviations: CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system.

Figure viewer

Figure 2 Glyoxylate metabolism in the hepatocyte and enzymatic deficiencies in primary hyperoxaluria. Primary hyperoxaluria types 1 and 2, associated with peroxisomal AGT and cytosolic GRHPR deficiency respectively, result in accumulation of glyoxylate, which is converted to oxalate by LDH. Primary hyperoxaluria 3 is caused by a defect in HOGA in mitochondria; mechanisms leading to increased oxalate levels are not well-defined. GO catalyses the conversion of glycolate to glyoxylate and glyoxylate to oxalate. RNA interference (RNAi)-based drugs targeting GO and LDH are potential therapies for patients with PH1. Abbreviations: AGT, alanine-glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase–hydroxypyruvate reductase; HOGA, 4-hydroxy-2-oxoglutarate aldolase; LDH, lactate dehydrogenase. Based on information in Cochat and Rumsby,23 Hoppe,2 and Devresse et al.22

Oxalate is absorbed in the gut via paracellular passive transport, but there is also strong evidence of active intestinal absorption and secretion via transcellular oxalate anion exchangers of the solute-linked carrier 26 (SCL26) family. The relative contribution of oxalate absorption involving paracellular and transcellular pathways and secretion determines the overall net oxalate movement across the intestine.8 SLC26A1 and SCL26A6 exchangers are expressed in the basolateral and apical membrane of enterocytes, respectively, allowing oxalate secretion into the intestinal lumen. SLC26A3 is an apical oxalate transporter mediating oxalate uptake.1,7 Studies suggest a remarkable adaptive capacity of the intestine to either actively absorb or secrete oxalate in response to local and systemic inputs integrated through the endocrine and autonomic nervous systems.8 Cholinergic regulation inhibits oxalate uptake through reduced expression‎ of SCL26A6 in human cell lines.8-10 A purinergic signaling system also regulates oxalate transport across digestive epithelia.11,12 In murine chronic kidney disease (CKD) models, Slc26a6-mediated enteric oxalate secretion is critical in lowering the body burden of oxalate.13

Plasma oxalate does not have any known function in the human body and is rapidly excreted by the kidney via glomerular filtration and tubular secretion. Both mechanisms are critical in regulating plasma oxalate levels.14,15 SCL26A6 is also located at the apical membrane of the proximal tubule and actively transports oxalate into the urinary filtrate. SLC26A1 is localized to the basolateral membrane of the tubular cell and is thought to reduce urinary oxalate secretion.1,7

Urinary oxalate excretion in healthy adults is influenced by dietary intake, and levels exceeding 40-45 mg/d (500 μmol/d) define hyperoxaluria.16 Oxaluria may also be quantified using the oxalate to creatinine ratio on a spot urine sample.17 Studies have shown a good correlation between spot level and 24-hour excretion, with no significant diurnal pattern of oxalate excretion.18,19 In individuals with stages 4 and 5 CKD, urinary oxalate excretion decreases and plasma oxalate starts to rise.20 Plasma oxalate levels are used to monitor primary hyperoxaluria patients with CKD and on dialysis before transplantation.21,22 Plasma oxalate levels should be <30 μmol/L at the end of each dialysis session because this is the threshold value for oversaturation of plasma calcium oxalate.5

However, accurate measurement of plasma oxalate concentration is challenging. Prompt acidification or freezing of samples and storage at −80°C until acidification is required to prevent conversion of plasma ascorbate to oxalate.20 Moreover, plasma oxalate levels do not correlate well with estimated glomerular filtration rate (eGFR) and show significant intraindividual variation in patients with primary hyperoxaluria.21

Primary Hyperoxaluria

Primary hyperoxaluria types 1, 2, and 3 are rare autosomal recessive inherited disorders of glyoxylate metabolism caused by pathogenic variants in AGXT, GRHPR, or HOGA1, respectively (Fig 2).2,23 The inability to metabolize glyoxylate leads to excessive hepatic production of oxalate and subsequent accumulation in various organs, including the kidney.2,23 Massive urolithiasis and/or calcium oxalate deposition in the renal parenchyma impairs kidney function and oxalate elimination. When the eGFR drops to ≤30-45 mL/min/1.73 m2, plasma oxalate increases, and oxalate may deposit in bone, kidneys, skin, retina, and the cardiovascular and central nervous systems. This dramatic condition is referred to as systemic oxalosis.2,22,23 Primary hyperoxaluria type 1 is the most common and severe form, generally leading to kidney failure during the first 3 decades of life. However, in some patients the condition is not diagnosed until adulthood with occasional or recurrent urolithiasis as the only clinical manifestations. The Gly170Arg and Phe152Ile variants in AGXT (a glycine to arginine substitution at amino acid 170 and a phenylalanine to isoleucine substitution at amino acid 152, respectively) are associated with adult-onset hyperoxaluria and with a less severe prognosis, partly due to the response to pyridoxine.23 Primary hyperoxaluria types 2 and 3 are generally milder, although patients with type 2 may present with CKD caused by recurrent urolithiasis.2,23

Prompt diagnosis of primary hyperoxaluria is essential to prevent downstream complications. Unfortunately, up to 50% of patients have advanced CKD or kidney failure at diagnosis, and approximately 10% are diagnosed after disease recurrence on a kidney allograft.2 As a result, the possibility of primary hyperoxaluria should be systematically considered among children with kidney stones or nephrocalcinosis and in adults with recurrent calcium oxalate stones. Patients with primary hyperoxaluria usually have a higher urinary oxalate excretion (>100 mg/d, >1.0 mmol/1.73 m2/d, or 1,000 μmol/d) than those with secondary hyperoxaluria (50-100 mg/d, 0.5-1.0 mmol/1.73 m2/d, or 500-1,000 μmol/d).2 In children, age-specific reference ranges for spot urinary oxalate to creatinine ratios are used.2,17 Measures of plasma oxalate level may be helpful in patients with CKD stage 3b because they generally increase only when the eGFR is below 30 mL/min/1.73 m2 in patients with CKD from other etiologies. The definitive diagnosis of primary hyperoxaluria is achieved by molecular genetic testing.2,23

The conservative therapeutic options in primary hyperoxaluria include massive fluid intake (tube or gastrostomy feeding in infants), calcium oxalate crystallization inhibitors, and vitamin B6 (pyridoxine) in primary hyperoxaluria type 1.23 To date, liver transplantation is the only established “curative” therapy to correct the metabolic defect contributing to excessive endogenous oxalate formation.2,22,23 Liver-kidney transplantation (simultaneously or sequentially) is the current standard of care in patients with primary hyperoxaluria type 1 and CKD. It should ideally be performed before the development of systemic oxalosis and related complications.22-24 Indeed, outcomes after kidney transplantation are improved by a substantial residual kidney function and by the absence of major systemic oxalate load.23 Oliguria should be avoided in the peritransplant period; in this respect, minimizing the risk of acute tubular necrosis of the graft may impact the choice of donor. In patients with kidney failure awaiting transplantation, intensive hemodialysis strategies limit systemic oxalate accumulation.22,23

New promising therapeutic agents are under investigation and are expected to dramatically influence the management and outcomes of patients with primary hyperoxaluria. Lumasiran is a RNA interference (RNAi)-based therapy that blocks the synthesis of oxalate glycolate oxidase and reduces oxidation of glycolate to glyoxylate, the immediate precursor of oxalate (Fig 2). In the phase 3 ILLUMINATE-A study, patients with primary hyperoxaluria type 1 receiving lumasiran showed a significant reduction in urinary oxalate excretion after 6 months of treatment in comparison with the placebo group.25 Two additional phase 3 trials testing the efficacy and safety of lumasiran are ongoing: ILLUMINATE-B (ClinicalTrials.gov identifier www.clinicaltrials.gov/ct2/show/NCT03905694) and ILLUMINATE-C (clinicaltrials.gov/ct2/show/NCT04152200).22 The US Food and Drug Administration and European Medicines Agency have recently approved lumasiran for the treatment of children and adults with primary hyperoxaluria type 1. Nedosiran, a RNAi therapy targeting lactate dehydrogenase and reducing conversion of glyoxylate to oxalate, is being tested in a phase 3 study (clinicaltrials.gov/ct2/show/NCT04042402). If these emerging therapies are confirmed to be efficient and safe in patients on dialysis and in kidney graft recipients, liver transplantation may perhaps no longer be required in the future.22

Secondary HyperoxaluriaCauses of Secondary Hyperoxaluria

Secondary hyperoxaluria results from (1) increased dietary oxalate or oxalate precursor intake, (2) fat malabsorption, and (3) decreased intestinal oxalate degradation due to alterations in gut microbiota (Fig 1; Box 1). Hyperoxaluria has been associated with increased intake of nuts, tea, Averrhoa carambola (star fruit) and bilimbi, rhubarb, chaga mushroom, spinach, and “green smoothies” and “juicing.”4 Ascorbic acid (vitamin C), ethylene glycol, naftidrofuryl oxalate (a vasodilator), and methoxyflurane (an anesthetic agent) all are precursors of oxalate, and excessive intake or exposure may lead to hyperoxaluria (Fig 3). Fat malabsorption from various causes (pancreatic disorders, Roux-en-Y bypass surgery, short bowel disease, Crohn disease, use of orlistat) leads to steatorrhea, calcium binding by fatty acids in the intestinal lumen, increased intestinal absorption of free oxalate, and higher ileal and colonic permeability to oxalate. Secondary hyperoxaluria may also be multifactorial. For example, cystic fibrosis leads to hyperoxaluria via malabsorption due to exocrine pancreatic insufficiency, defects in oxalate exchangers, and microbiota perturbations associated with frequent antibiotic use.26,27

Figure viewer

Figure 3 Oxalate precursors and metabolic pathways.

Box 1

Causes of Secondary Hyperoxaluria and Oxalate Nephropathy

aData mostly obtained from murine models.

Increased intestinal oxalate absorption

•

Chronic pancreatitis

•

Pancreatectomy

•

Use of orlistat (lipase inhibitor)

•

Roux-en-Y gastric bypass

•

Small bowel resection

•

Crohn’s disease

•

Celiac disease

•

Cystic fibrosis

•

Use of somatostatin analogue

Increased dietary oxalate or precursor intake

•

Rhubarb, Averrhoa carambola (star fruit), Averrhoa bilimbi, tea, nuts, “juicing”

•

Vitamin C, ethylene glycol, methoxyflurane, naftidrofuryl oxalate

Decreased intestinal bacterial oxalate degradation

•

Antibiotic use

Others

•

Obesity, genetic variations in oxalate transporters?a

Obesity and the metabolic syndrome are also associated with calcium oxalate nephrolithiasis.28,29 Obese mice show local and systemic inflammation, which contributes to reduced active transcellular oxalate secretion into the bowel via anion exchanger Slc26a6 and enhanced gastrointestinal paracellular absorption of oxalate.29-31 Obesity-associated cholinergic activity also leads to Slc26a6 inhibition.10 Increased dietary ingestion of oxalate and alterations in intestinal microbiota may further contribute to obesity-associated hyperoxaluria.29,31 Moreover, urinary excretion of oxalate is higher in individuals with diabetes mellitus.3 Plasma levels of glyoxylate and glyoxal (a protein glycation product), potential precursors of oxalate, are higher in diabetic patients, possibly contributing to hyperoxaluria.3

Secondary hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation,16 contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy5 (Fig 1). In contrast to primary forms of the disease, characterized by a high systemic oxalate load, secondary hyperoxaluria only leads to extrarenal deposition of oxalate in very rare cases, such as in severe Crohn disease.14

Secondary Hyperoxaluria and Urolithiasis

Hyperoxaluria is the main risk factor for calcium oxalate urolithiasis.5 Supersaturation of calcium oxalate is 10 times more dependent on a rise in urinary oxalate than on an equimolar rise of urinary calcium concentration.5 Urinary oxalate excretion correlates with the risk of developing a kidney stone event.32 In patients with malabsorption, fluid loss and a low urinary pH and citrate level also contribute to the pathogenesis of urolithiasis.27,32 A meta-analysis of 12 observational studies showed a significantly higher risk of stone formation after Roux-en-Y gastric bypass surgery with a pooled relative risk of 1.79 (95% CI, 1.54-2.10).33 Similarly, a recently published review reported a stone incidence ranging from 2% to 38% in patients with malabsorptive states other than after bariatric surgery.27

The risk of calcium oxalate urolithiasis is also associated with intestinal microbiota composition. Healthy oxalate homeostasis in the gastrointestinal tract involves a collaborative effort between numerous bacterial species. In fecal samples from healthy individuals, metagenomics studies reveal a network of bacterial taxa co-occurring with Oxalobacter formigenes, which are less represented in urinary stone formers.34 This would explain why the absence of O formigenes is not causative of stone disease and why colonization with the bacteria failed to reduce urinary oxalate excretion in interventional studies.35 Similarly, children who are calcium oxalate stone formers have fewer oxalate-degrading and butyrate-forming bacterial taxa in the gut, leading to hyperoxaluria. Butyrate maintains the gut mucosal barrier and regulates intestinal SLC26 oxalate transporters.36

In mice, Slc26a1 gene deletion causes a reduction in intestinal secretion of oxalate, leading to hyperoxalemia and hyperoxaluria.37 Human SLC26A1 mutations may presumably lead to urolithiasis via similar mechanisms.1 Additionally, polymorphisms of SLC26A6 in humans may explain accelerated lithogenesis in distinct populations.16,38

Secondary Hyperoxaluria and Oxalate Nephropathy

Oxalate nephropathy is a severe condition resulting from deposition of calcium oxalate crystals in kidney tissue, which causes tubular-interstitial injury and fibrosis, acute kidney injury (AKI), and/or CKD26,39-41 (Fig 4). Most investigators have used the following diagnostic criteria for oxalate nephropathy: (1) progressive kidney disease, (2) oxalate crystal deposition with tubular injury and interstitial nephritis, and (3) exclusion of other etiologies of kidney disease (aside from vascular and/or diabetes-associated nephropathy). A hyperoxaluria-enabling condition should ideally also be identified26,39-41 (Box 2).

Figure viewer

Figure 4 Oxalate nephropathy, kidney biopsy sample. (A) Intratubular translucent polyhedral or rhomboid crystals (black arrows) on light microscopy (hematoxylin and eosin stain, original magnification, ×20). (B) Crystals shown as birefringent under polarized light (original magnification, ×5). Biopsy also shows acute tubular injury and mild interstitial inflammation.

Box 2

Definition of Oxalate Nephropathy

1.

Progressive kidney disease.

2.

Deposition of calcium oxalate crystals (birefringent on polarized light) within tubular epithelial cells, tubular lumens, and less frequently in the interstitium, associated with tubular injury and interstitial nephritis.

3.

Exclusion of other causes of kidney disease (apart from nonspecific microvascular lesions and/or diabetes-associated glomerular lesions).

4.

Ideally, a hyperoxaluria enabling-condition should be identified.

The preval‎ence of oxalate nephropathy is unknown. We recently reported 22 cases (1%) of oxalate nephropathy out of 2,265 consecutive native kidney biopsies performed during a 9-year period.40 Table 1 shows the clinical characteristics and outcomes of patients with oxalate nephropathy reported in 4 case series and 1 systematic review.26,39-42 Upon presentation, most patients had hypertension, diabetes, and/or a history of CKD. The latter may result from past subclinical deposition of oxalate crystals or represent a predisposing factor because of reduced excretion of oxalate.40

Nasr et al, 2008a,39Cartery et al, 2011a,41Lumlertgul et al, 201826Buysschaert et al, 202040Yang et al, 202042

Table 1

Published Cases Series of Secondary Oxalate Nephropathy

Values for categorical variables are given as n (%) or count; for continuous values as mean. Abbreviations: NA, not available (or too few numbers); OxN, oxalate nephropathy; RAAS, renin-angiotensin-aldosterone system; UPCR, urinary protein-creatinine ratio.

a

Included in the systematic review by Lumlertgul et al.26

b

Patients with unknown causes of oxalate nephropathy and those with short duration of exposure (<30 days) to hyperoxaluria-enabling conditions were excluded.

c

Quantitative data from 57 case reports of oxalate nephropathy not reported in Lumlertgul et al.26

d

Twenty-one of 22 patients with available clinical data.

e

Patients with other causes of CKD such as lupus nephritis were included.

f

Some patients had 2 identified hyperoxaluria-enabling conditions.

g

No systematic gastrointestinal and/or genetic workup reported.

h

Normal value ≤ 45 mg/d.

i

Normal value < 32 mg/g.

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Approximately two-thirds of the patients have malabsorption-associated hyperoxaluria.26,40 We found that chronic pancreatitis and gastric bypass were the most common causes of oxalate nephropathy (48%).40 Of note, Lumlertgul et al26 excluded patients with a short duration of exposure (<30 days) to the hyperoxaluria-enabling conditions (ie, vitamin C and oxalate-rich foods). Interestingly, hyperoxaluria-enabling conditions (ie, malabsorptive states) may be long standing; we reported the development of oxalate nephropathy a mean of 8 years after gastric bypass in 5 patients and 1 and 8 years after orlistat initiation in 2 patients.40 This suggests that the combination of the hyperoxaluria-enabling condition with an additional factor or trigger may lead to crystal formation and kidney damage40,4143,44 (Fig 1). Factors such as acute dehydration, diuretic use, inflammation, antibiotic use, or high dietary oxalate intake may increase the urinary oxalate concentration. Renin-angiotensin-aldosterone system (RAAS) blocker use is also highly preval‎ent in patients presenting with oxalate nephropathy and may favor oxalate crystal-associated kidney injury via the reduction of glomerular filtration fraction.39-41

Clinical presentation of oxalate nephropathy varies across the spectrum of AKI, AKI on CKD, and CKD. Patients present with kidney failure in most cases (mean serum creatinine level of 4.9-8.0 mg/dL). Moderate to profound hypocalcemia was reported in 9 of 12 patients with oxalate nephropathy associated with chronic pancreatitis and may evoke the diagnosis.41 Kidney biopsy shows variable degrees of acute tubular necrosis, interstitial nephritis, and chronic damage. In addition, a substantial proportion of patients have glomerular changes (mostly glomerulosclerosis, associated or not with diabetes). The prognosis of oxalate nephropathy is variable, with approximately half of patients rapidly reaching kidney failure. The outcome may be more favorable in patients presenting with oxalate nephropathy secondary to acute ingestion of high amounts of dietary oxalate.4

Calcium oxalate crystals are most commonly found in proximal and distal tubules in the cortex. They are deposited within tubular lumens, tubular epithelial cells, and less frequently in the interstitium.45 Calcium oxalate crystals are strongly birefringent on polarized light, unlike calcium phosphate crystals46 (Fig 4). Of note, scarce calcium oxalate crystals may be found in tubules in patients with other causes of kidney damage, especially in the setting of reduced eGFR.31,39,41,42 We thus recently suggested adding an oxalate crystal to glomerulus ratio of ≥0.25 in the definition of oxalate nephropathy. Indeed, we found that this ratio separates patients with oxalate nephropathy from those with other well-documented kidney diseases and scarce calcium oxalate crystals.40 Further studies are needed to validate this criterion for distinguishing oxalate nephropathy from nonspecific oxalate deposition. It is also worth noting that although the term “nephrocalcinosis” is often used to refer to calcium salt deposits in kidney tissue, it should probably be used for calcium phosphate and not for calcium oxalate deposition.47

Studies have shown that different crystals such as calcium oxalate, uric acid, and monoclonal light chains share cellular and molecular mechanisms leading to kidney damage, such as stimulation of the NLRP3 inflammasome, a multiprotein oligomer that triggers interleukin-1β (IL-1β)-induced inflammation.48-51 In mice, Nlrp3 deletion successfully protects from progressive kidney failure secondary to ingestion of a diet high in soluble oxalate.51 Nlrp3 inhibition in hyperoxaluric mice protects against calcium oxalate deposition and CKD via a shift in the phenotype of renal macrophages, promoting anti-inflammatory rather than proinflammatory and profibrotic responses. The IL-1 inhibitor anakinra did not show such a protective effect, suggesting that Nlrp3 contributes to calcium oxalate deposition–induced kidney fibrosis independently from IL-1-mediated tissue injury.52

The characteristics of crystal deposition condition the clinical presentation. Acute supersaturation, rapid crystal formation, direct and indirect kidney epithelial cytotoxicity, and inflammation-driven cell necrosis lead to acute kidney damage. By contrast, ongoing mild supersaturation generating subacute crystal plug formation in distal tubules or collecting ducts leads to CKD.48 Crystal deposition is a potent driver of kidney fibrosis, leading to loss of kidney function.48,49

Hyperoxaluria and Progression of CKD

Given the potential nephrotoxicity of oxalate at high levels, Waikar et al53 hypothesized that a higher urinary oxalate, even within the reference range, would be associated with a higher risk of CKD progression. They tested this hypothesis in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective multicenter cohort study of risk factors for cardiovascular disease, progression of CKD, and mortality in patients with mild to moderate CKD. Among 3,123 participants, they showed that higher versus lower 24-hour urinary oxalate excretion (at the 40th percentile) was independently associated with a 32% higher risk of CKD progression and 37% higher risk of kidney failure.53

The association between hyperoxaluria and faster decline in eGFR was also shown in a small cohort of patients with chronic pancreatitis.54 Similarly, previous studies have suggested that calcium oxalate deposition in kidney graft biopsies may be associated with lesser graft function beyond the early posttransplant period.55,56 Urinary oxalate excretion may thus be a potential risk factor for progression in common forms of CKD. Likewise, it has been suggested that urinary oxalate may be a potential mediator of CKD development and progression in individuals with diabetes or obesity.3 Altogether, if these results are confirmed, the question of whether lowering urinary oxalate excretion could be beneficial in slowing CKD progression would need to be addressed.

Management of Secondary Hyperoxaluria and Oxalate Nephropathy

Treatment should be initiated rapidly, starting with high fluid intake16,27,57 (Table 2). The goal is to obtain a daily urine output in excess of 2-3 liters in order to reduce urinary supersaturation with oxalate. Dietary measures to reduce intestinal oxalate absorption include a low-oxalate, low-fat, and normal calcium diet.27 Additionally, calcium supplements are given orally to reduce the bioavailability of intestinal oxalate and its absorption.27,58 Crystallization inhibitors such as citrate may also be used.59 Importantly, all studies performed with these interventions were performed on small numbers of individuals for a limited periods of time, often without control groups or randomization.60

TreatmentRationaleSupporting evidence

High fluid intake (urine output >2-3 L/d)	Reduces urine calcium oxalate supersaturation.	Reduces stone formation.67,68
Low-oxalate diet	Reduces bioavailability of intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies; caveat: comparisons were based on a low-oxalate diet compared to a very-high-oxalate diet.60,69,70
Low-fat diet	Reduces intestinal oxalate absorption (by increasing bioavailability of intestinal calcium).	Reduces urinary oxalate excretion in small studies.70,71
Normal-calcium diet	Avoid low-calcium diets, which lead to more free intestinal oxalate.	Reduces urinary oxalate excretion in small-sized studies.69,72
Calcium supplements	Reduce bioavailability of intestinal oxalate and its absorption.	Reduces urinary oxalate excretion but may lead to hypercalciuria.72-74 Calcium citrate may be more bioavailable than calcium carbonate.75
Cholestyramine	Binds intestinal bile acids, reduces diarrhea, and binds oxalate in vitro.	Studies show contradicting results.70,73,76
Oxalobacter formigenes administration	Increases intestinal oxalate degradation.	Reduces urinary oxalate excretion in rat model61,77 and plasma oxalate levels in dialysis patients with primary hyperoxaluria (phase 2 study).35
Oxalate decarboxylase	Degrades intestinal oxalate.	Reduces urinary oxalate excretion in rat model78 and in phase 3 pilot study in humans.62
NLRP3-specific inflammasome inhibitor	Reduces crystal-induced kidney damage.	Reduces calcium-oxalate crystal-induced kidney fibrosis in mouse model.63

Table 2

Current and Potential Therapies of Secondary Hyperoxaluria

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The therapeutic options currently being tested include oral administration of intestinal bacteria and/or enzymes capable of degrading oxalate. O formigenes administration has been shown to reduce urinary oxalate excretion in animal models with enteric hyperoxaluria.61 In humans, this strategy has only been tested in patients with primary hyperoxaluria.35 Oxalate decarboxylase, an oxalate-degrading enzyme, was shown in a pilot phase 3 open-label study to reduce urinary oxalate excretion among 16 patients with both secondary hyperoxaluria and a history of kidney stones.62 The results will need to be confirmed in the phase 3 follow-up randomized controlled trial. A better understanding of the molecular mechanisms of crystal nephropathies may also lead to the development of targeted therapies.48 As previously mentioned, a NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.63

A diagnostic workup is fundamental to treating the underlying cause of hyperoxaluria. Hyperoxaluria-enabling conditions may be long standing but paucisymptomatic. We have shown, for example, that chronic pancreatitis may frequently be diagnosed only after oxalate nephropathy, even in kidney transplant recipients.40,41,64 Morpho-constitutional analysis of kidney stones, combining stereomicroscopy and Fourier-transform infrared spectroscopy, may help in determining the cause of hyperoxaluria.65 Dietary hyperoxaluria may be difficult to identify because oxalate content is not provided by food manufacturers and food tables often report conflicting data on oxalate content.60 In patients with hyperoxaluria and/or oxalate nephropathy of unknown etiology, primary hyperoxaluria must not be overlooked (see the previous section).66

Treatment of the underlying cause of secondary hyperoxaluria includes withdrawal of oxalate-rich foods or precursors, pancreatic enzyme therapy, intensification of Crohn disease therapy, and in some cases reversal of gastric bypass. Identification and management of the cause of secondary hyperoxaluria is also important to minimize the risk of recurrence of oxalate nephropathy after kidney transplantation. Therapeutic considerations concerning patients with secondary hyperoxaluria on dialysis and during the peritransplantation period are beyond the scope of this review. In addition, further studies are needed to determine the clinical significance of hyperoxaluria in asymptomatic patients with hyperoxaluria-enabling conditions in order to determine the subset with the greatest likelihood of deriving benefit from treatment aimed at preventing renal complications.

Conclusions

Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and associated kidney damage. Prompt recognition and management of primary and secondary hyperoxaluria is crucial. Fortunately, novel targeted therapeutic approaches are on the horizon for patients with primary hyperoxaluria.

Article InformationAuthors’ Full Names and Academic Degrees

Nathalie Demoulin, MD, Selda Aydin, MD, PhD, Valentine Gillion, MD, Johann Morelle, MD, PhD, and Michel Jadoul, MD.

Support

None.

Financial Disclosure

The authors declare that they have no relevant financial interests.

Peer Review

Received March 28, 2021. Eval‎uated by 3 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor and a Deputy Editor. Accepted in revised form July 27, 2021.

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