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American Journal of Kidney Diseases

Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review

  • Nathalie Demoulin
    Correspondence
    Address for Correspondence: Nathalie Demoulin, MD, Division of Nephrology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Brussels, Belgium.
    Affiliations
    Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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  • Selda Aydin
    Affiliations
    Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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  • Valentine Gillion
    Affiliations
    Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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  • Johann Morelle
    Affiliations
    Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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  • Michel Jadoul
    Affiliations
    Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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Published:September 08, 2021DOI:https://doi.org/10.1053/j.ajkd.2021.07.018
      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

      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 oxalate
      • Sayer J.A.
      Progress in understanding the genetics of calcium-containing nephrolithiasis.
      ,
      • Hoppe B.
      An update on primary hyperoxaluria.
      (Fig 2). Dietary sources rich in oxalate include leafy vegetables, nuts, tea, and fruits rich in vitamin C.
      • Efe O.
      • Verma A.
      • Walkar S.S.
      Urinary oxalate as a potential mediator of kidney disease in diabetes mellitus and obesity.
      ,
      • Glew R.H.
      • Sun Y.
      • Horowitz B.L.
      • et al.
      Nephropathy in dietary hyperoxaluria: a potentially preventable acute or chronic kidney disease.
      Average daily oxalate intake is approximately 80-130 mg.
      • Hoppe B.
      • Leumann E.
      • von Unruh G.
      • Laube N.
      • Hesse A.
      Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria.
      ,
      • Holmes R.P.
      • Kenney M.
      Estimation of the oxalate content of foods and daily oxalate intake.
      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 formigenes
      • Sayer J.A.
      Progress in understanding the genetics of calcium-containing nephrolithiasis.
      ,
      • Ermer T.
      • Eckardt K.U.
      • Aronson P.S.
      • Knauf F.
      Oxalate, inflammasome, and progression of kidney disease.
      (Fig 1).
      Figure thumbnail gr1
      Figure 1Causes 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,
      • Sayer J.A.
      Progress in understanding the genetics of calcium-containing nephrolithiasis.
      Ermer et al,
      • Ermer T.
      • Eckardt K.U.
      • Aronson P.S.
      • Knauf F.
      Oxalate, inflammasome, and progression of kidney disease.
      Hoppe et al,
      • Hoppe B.
      • Leumann E.
      • von Unruh G.
      • Laube N.
      • Hesse A.
      Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria.
      and Aronson et al.
      • Aronson P.S.
      Essential roles of CFEX-mediated Cl-oxalate exchange in proximal tubule NACl transport and prevention of urolithiasis.
      Abbreviations: CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system.
      Figure thumbnail gr2
      Figure 2Glyoxylate 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,
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      Hoppe,
      • Hoppe B.
      An update on primary hyperoxaluria.
      and Devresse et al.
      • Devresse A.
      • Cochat P.
      • Godefroid N.
      • Kanaan N.
      Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives.
      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.
      • Whittamore J.M.
      • Hatch M.
      The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man.
      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.
      • Sayer J.A.
      Progress in understanding the genetics of calcium-containing nephrolithiasis.
      ,
      • Ermer T.
      • Eckardt K.U.
      • Aronson P.S.
      • Knauf F.
      Oxalate, inflammasome, and progression of kidney disease.
      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.
      • Whittamore J.M.
      • Hatch M.
      The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man.
      Cholinergic regulation inhibits oxalate uptake through reduced expression of SCL26A6 in human cell lines.
      • Whittamore J.M.
      • Hatch M.
      The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man.
      • Hassan H.A.
      • Mentone S.
      • Karniski L.P.
      • Rajendran V.M.
      • Aronson P.S.
      Regulation of anion exchanger Slc26a6 by protein kinase C.
      • Hassan H.A.
      • Cheng M.
      • Aronson P.S.
      Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells.
      A purinergic signaling system also regulates oxalate transport across digestive epithelia.
      • Jung D.
      • Alshaikh A.
      • Ratakonda S.
      • et al.
      Adenosinergic signaling inhibits oxalate transport by human intestinal Caco2-BBE cells through the A2B adenosine receptor.
      ,
      • Bucheimer R.E.
      • Linden J.
      Purinergic regulation of epithelial transport.
      In murine chronic kidney disease (CKD) models, Slc26a6-mediated enteric oxalate secretion is critical in lowering the body burden of oxalate.
      • Neumeier L.I.
      • Thomson R.B.
      • Reichel M.
      • Eckardt K.U.
      • Aronson P.S.
      • Knaud F.
      Enteric oxalate secretion mediated by Slc26a6 defends against hyperoxalemia in murine models of chronic kidney disease.
      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.
      • Bhasin B.
      • Urekli H.M.
      • Atta M.G.
      Primary and secondary hyperoxaluria: understanding the enigma.
      ,
      • Bergsland K.J.
      • Zisman A.L.
      • Asplin J.R.
      • et al.
      Evidence for net renal tubule oxalate secretion in patients with calcium oxalate stones.
      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.
      • Sayer J.A.
      Progress in understanding the genetics of calcium-containing nephrolithiasis.
      ,
      • Ermer T.
      • Eckardt K.U.
      • Aronson P.S.
      • Knauf F.
      Oxalate, inflammasome, and progression of kidney disease.
      Urinary oxalate excretion in healthy adults is influenced by dietary intake, and levels exceeding 40-45 mg/d (500 μmol/d) define hyperoxaluria.
      • Robijn S.
      • Hoppe B.
      • Vervaet B.A.
      • D’Haese P.C.
      • Verhulst A.
      Hyperoxaluria: a gut-kidney axis?.
      Oxaluria may also be quantified using the oxalate to creatinine ratio on a spot urine sample.
      • Habbig S.
      • Beck B.B.
      • Hoppe B.
      Nephrocalcinosis and urolithiasis in children.
      Studies have shown a good correlation between spot level and 24-hour excretion, with no significant diurnal pattern of oxalate excretion.
      • Von Schnakenburg C.
      • Byrd D.J.
      • Latta K.
      • Reusz G.S.
      • Graf D.
      • Brodehl J.
      Determination of oxalate excretion in spot urines of health children by ion chromatography.
      ,
      • Elgstoen K.B.P.
      • Woldseth B.
      • Hoie K.
      • Morkid L.
      Liquid chromatography-tandem mass spectrometry determination of oxalate in spot urine.
      In individuals with stages 4 and 5 CKD, urinary oxalate excretion decreases and plasma oxalate starts to rise.
      • Pfau A.
      • Wytopil M.
      • Chauhan K.
      • et al.
      Assessment of plasma oxalate concentration in patients with CKD.
      Plasma oxalate levels are used to monitor primary hyperoxaluria patients with CKD and on dialysis before transplantation.
      • Hillebrand P.
      • Hoppe B.
      Plasma oxalate levels in primary hyperoxaluria type 1 show significant intra-individual variation and do not correlate with kidney function.
      ,
      • Devresse A.
      • Cochat P.
      • Godefroid N.
      • Kanaan N.
      Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives.
      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.
      • Hoppe B.
      • Leumann E.
      • von Unruh G.
      • Laube N.
      • Hesse A.
      Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria.
      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.
      • Pfau A.
      • Wytopil M.
      • Chauhan K.
      • et al.
      Assessment of plasma oxalate concentration in patients with CKD.
      Moreover, plasma oxalate levels do not correlate well with estimated glomerular filtration rate (eGFR) and show significant intraindividual variation in patients with primary hyperoxaluria.
      • Hillebrand P.
      • Hoppe B.
      Plasma oxalate levels in primary hyperoxaluria type 1 show significant intra-individual variation and do not correlate with kidney function.

      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).
      • Hoppe B.
      An update on primary hyperoxaluria.
      ,
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      The inability to metabolize glyoxylate leads to excessive hepatic production of oxalate and subsequent accumulation in various organs, including the kidney.
      • Hoppe B.
      An update on primary hyperoxaluria.
      ,
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      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.
      • Hoppe B.
      An update on primary hyperoxaluria.
      ,
      • Devresse A.
      • Cochat P.
      • Godefroid N.
      • Kanaan N.
      Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives.
      ,
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      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.
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      Primary hyperoxaluria types 2 and 3 are generally milder, although patients with type 2 may present with CKD caused by recurrent urolithiasis.
      • Hoppe B.
      An update on primary hyperoxaluria.
      ,
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      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.
      • Hoppe B.
      An update on primary hyperoxaluria.
      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).
      • Hoppe B.
      An update on primary hyperoxaluria.
      In children, age-specific reference ranges for spot urinary oxalate to creatinine ratios are used.
      • Hoppe B.
      An update on primary hyperoxaluria.
      ,
      • Habbig S.
      • Beck B.B.
      • Hoppe B.
      Nephrocalcinosis and urolithiasis in children.
      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.
      • Hoppe B.
      An update on primary hyperoxaluria.
      ,
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      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.
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      To date, liver transplantation is the only established “curative” therapy to correct the metabolic defect contributing to excessive endogenous oxalate formation.
      • Hoppe B.
      An update on primary hyperoxaluria.
      ,
      • Devresse A.
      • Cochat P.
      • Godefroid N.
      • Kanaan N.
      Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives.
      ,
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      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.
      • Devresse A.
      • Cochat P.
      • Godefroid N.
      • Kanaan N.
      Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives.
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      • Cochat P.
      • Gaulier J.M.
      • Koch Nogueira P.C.
      • et al.
      Combined liver-kidney transplantation in primary hyperoxaluria type 1.
      Indeed, outcomes after kidney transplantation are improved by a substantial residual kidney function and by the absence of major systemic oxalate load.
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      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.
      • Devresse A.
      • Cochat P.
      • Godefroid N.
      • Kanaan N.
      Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives.
      ,
      • Cochat P.
      • Rumsby G.
      Primary hyperoxaluria.
      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.
      • Garrelfs S.F.
      • Frishberg Y.
      • Huston S.A.
      • et al.
      Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1.
      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).
      • Devresse A.
      • Cochat P.
      • Godefroid N.
      • Kanaan N.
      Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives.
      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.
      • Devresse A.
      • Cochat P.
      • Godefroid N.
      • Kanaan N.
      Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives.

      Secondary Hyperoxaluria

      Causes 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.”
      • Glew R.H.
      • Sun Y.
      • Horowitz B.L.
      • et al.
      Nephropathy in dietary hyperoxaluria: a potentially preventable acute or chronic kidney disease.
      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.
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      ,
      • Witting C.
      • Langman C.B.
      • Assimos D.
      • et al.
      Pathophysiology and treatment of enteric hyperoxaluria.
      Causes of Secondary Hyperoxaluria and Oxalate Nephropathy
      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
      aData mostly obtained from murine models.
      Figure thumbnail gr3
      Figure 3Oxalate precursors and metabolic pathways.
      Obesity and the metabolic syndrome are also associated with calcium oxalate nephrolithiasis.
      • Sakhaee K.
      Nephrolithiasis as a systemic disorder.
      ,
      • Sakhaee K.
      Unravelling the mechanisms of obesity-induced hyperoxaluria.
      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.
      • Sakhaee K.
      Unravelling the mechanisms of obesity-induced hyperoxaluria.
      • Bashir M.
      • Meddings J.
      • Alshaikh A.
      • et al.
      Enhanced gastrointestinal passive paracellular permeability contributes to the obesity-associated hyperoxaluria.
      • Amin R.
      • Asplin J.
      • Jung D.
      • et al.
      Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria.
      Obesity-associated cholinergic activity also leads to Slc26a6 inhibition.
      • Hassan H.A.
      • Cheng M.
      • Aronson P.S.
      Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells.
      Increased dietary ingestion of oxalate and alterations in intestinal microbiota may further contribute to obesity-associated hyperoxaluria.
      • Sakhaee K.
      Unravelling the mechanisms of obesity-induced hyperoxaluria.
      ,
      • Amin R.
      • Asplin J.
      • Jung D.
      • et al.
      Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria.
      Moreover, urinary excretion of oxalate is higher in individuals with diabetes mellitus.
      • Efe O.
      • Verma A.
      • Walkar S.S.
      Urinary oxalate as a potential mediator of kidney disease in diabetes mellitus and obesity.
      Plasma levels of glyoxylate and glyoxal (a protein glycation product), potential precursors of oxalate, are higher in diabetic patients, possibly contributing to hyperoxaluria.
      • Efe O.
      • Verma A.
      • Walkar S.S.
      Urinary oxalate as a potential mediator of kidney disease in diabetes mellitus and obesity.
      Secondary hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation,
      • Robijn S.
      • Hoppe B.
      • Vervaet B.A.
      • D’Haese P.C.
      • Verhulst A.
      Hyperoxaluria: a gut-kidney axis?.
      contributing to urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy
      • Hoppe B.
      • Leumann E.
      • von Unruh G.
      • Laube N.
      • Hesse A.
      Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria.
      (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.
      • Bhasin B.
      • Urekli H.M.
      • Atta M.G.
      Primary and secondary hyperoxaluria: understanding the enigma.

      Secondary Hyperoxaluria and Urolithiasis

      Hyperoxaluria is the main risk factor for calcium oxalate urolithiasis.
      • Hoppe B.
      • Leumann E.
      • von Unruh G.
      • Laube N.
      • Hesse A.
      Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria.
      Supersaturation of calcium oxalate is 10 times more dependent on a rise in urinary oxalate than on an equimolar rise of urinary calcium concentration.
      • Hoppe B.
      • Leumann E.
      • von Unruh G.
      • Laube N.
      • Hesse A.
      Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria.
      Urinary oxalate excretion correlates with the risk of developing a kidney stone event.

      D’Costa MR, Kausz AT, Carroll KJ, et al. Subsequent urinary stone events are predicted by the magnitude of urinary oxalate excretion in enteric hyperoxaluria. Nephrol Dial Transplant. Published online December 26, 2020. https://doi.org/10.1093/ndt/gfaa281

      In patients with malabsorption, fluid loss and a low urinary pH and citrate level also contribute to the pathogenesis of urolithiasis.
      • Witting C.
      • Langman C.B.
      • Assimos D.
      • et al.
      Pathophysiology and treatment of enteric hyperoxaluria.
      ,

      D’Costa MR, Kausz AT, Carroll KJ, et al. Subsequent urinary stone events are predicted by the magnitude of urinary oxalate excretion in enteric hyperoxaluria. Nephrol Dial Transplant. Published online December 26, 2020. https://doi.org/10.1093/ndt/gfaa281

      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).
      • Upala S.
      • Jaruvongvanich V.
      • Sanguankeo A.
      Risk of nephrolithiasis, hyperoxaluria, and calcium oxalate supersaturation increased after Roux-en-Y gastric bypass surgery: a systemic review and meta-analysis.
      Similarly, a recently published review reported a stone incidence ranging from 2% to 38% in patients with malabsorptive states other than after bariatric surgery.
      • Witting C.
      • Langman C.B.
      • Assimos D.
      • et al.
      Pathophysiology and treatment of enteric hyperoxaluria.
      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.
      • Miller A.W.
      • Choy D.
      • Penniston K.L.
      • Lange D.
      Inhibition of urinary stone disease by a multi-species bacterial network ensures healthy oxalate homeostasis.
      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.
      • Hoppe B.
      • Pellikka P.A.
      • Dehmel B.
      • Banos A.
      • Lindner E.
      • Herberg U.
      Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria type 1 and end-stage renal disease: a phase II study.
      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.
      • Denburg M.R.
      • Koepsell K.
      • Lee J.J.
      • Gerber J.
      • Bittinger K.
      • Tasian G.E.
      Perturbations of the gut microbiome and metabolome in children with calcium oxalate kidney stone disease.
      In mice, Slc26a1 gene deletion causes a reduction in intestinal secretion of oxalate, leading to hyperoxalemia and hyperoxaluria.
      • Dawon P.A.
      • Russell C.S.
      • Lee S.
      • et al.
      Urolithiasis and hepatoxicity are linked to the anion transport Sat1 in mice..
      Human SLC26A1 mutations may presumably lead to urolithiasis via similar mechanisms.
      • Sayer J.A.
      Progress in understanding the genetics of calcium-containing nephrolithiasis.
      Additionally, polymorphisms of SLC26A6 in humans may explain accelerated lithogenesis in distinct populations.
      • Robijn S.
      • Hoppe B.
      • Vervaet B.A.
      • D’Haese P.C.
      • Verhulst A.
      Hyperoxaluria: a gut-kidney axis?.
      ,
      • Clark J.S.
      • Vandorpe D.H.
      • Chernova M.N.
      • et al.
      Species differences in Cl affinity and in electrogenicity of SLC26A6-mediated oxalate/Cl exchange correlate with the distinct human and mouse susceptibilities to nephrolithiasis.

      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 CKD
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      ,
      • Nasr S.H.
      • D’Agati V.D.
      • Said S.M.
      • et al.
      Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      (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 identified
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      ,
      • Nasr S.H.
      • D’Agati V.D.
      • Said S.M.
      • et al.
      Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      (Box 2).
      Figure thumbnail gr4
      Figure 4Oxalate 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.
      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.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      Table 1 shows the clinical characteristics and outcomes of patients with oxalate nephropathy reported in 4 case series and 1 systematic review.
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      ,
      • Nasr S.H.
      • D’Agati V.D.
      • Said S.M.
      • et al.
      Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      • Yang Y.
      • Shrame P.D.
      • Nair V.
      • et al.
      Kidney oxalate crystal deposition in adult patients: a relatively common finding.
      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.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      Table 1Published Cases Series of Secondary Oxalate Nephropathy
      Nasr et al, 2008
      Included in the systematic review by Lumlertgul et al.26
      ,
      • Nasr S.H.
      • D’Agati V.D.
      • Said S.M.
      • et al.
      Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure.
      Cartery et al, 2011
      Included in the systematic review by Lumlertgul et al.26
      ,
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      Lumlertgul et al, 2018
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      Buysschaert et al, 2020
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      Yang et al, 2020
      • Yang Y.
      • Shrame P.D.
      • Nair V.
      • et al.
      Kidney oxalate crystal deposition in adult patients: a relatively common finding.
      Included casesOxN associated with gastric bypassOxN associated with chronic pancreatitisReview of OxN case series, 1950-2018
      Patients with unknown causes of oxalate nephropathy and those with short duration of exposure (<30 days) to hyperoxaluria-enabling conditions were excluded.
      All-cause OxNAll-cause OxN
      No. of patients111251
      Quantitative data from 57 case reports of oxalate nephropathy not reported in Lumlertgul et al.26
      21
      Twenty-one of 22 patients with available clinical data.
      25
      Patients with other causes of CKD such as lupus nephritis were included.
      Patient characteristics
      Age, y6167566164
      Male sex5 (45%)9 (75%)30 (59%)14 (67%)13 (52%)
      Diabetes9 (82%)9 (75%)NA12 (57%)16 (64%)
      Hypertension11 (100%)8 (67%)NA16 (76%)19 (76%)
      Prior CKD7 (64%)7 (58%)NA13 (62%)NA
      Last eGFR, mL/min/1.73 m257NA36NA
      RAAS inhibitor use3 (30%)8 (67%)NA8 (38%)NA
      Diuretic use3 (30%)5 (42%)NA9 (43%)NA
      Kidney allograft0 (0)1 (8%)3 (6%)0 (0)3 (12%)
      Cause of OxN
      Malabsorptive state11 (100%)12 (100%)45 (88%)
      Some patients had 2 identified hyperoxaluria-enabling conditions.
      15 (71%)10 (40%)
      Increased intake of oxalate or precursor10 (20%)
      Some patients had 2 identified hyperoxaluria-enabling conditions.
      3 (14%)4 (16%)
      Unknown cause3 (14%)11 (44%)
      No systematic gastrointestinal and/or genetic workup reported.
      Duration of hyperoxaluria-predisposing condition, y2.810NA6.2NA
      Biological data at presentation
      Serum creatinine, mg/dL6.56.64.98.06.3
      Urinary oxalate, mg/24 h
      Normal value ≤ 45 mg/d.
      NA8085NANA
      Urinary oxalate-creatinine ratio, mg/g
      Normal value < 32 mg/g.
      NANANA86NA
      Urinary protein, g/d1.40.3NANANA
      UPCR (g/g)NANANA1.40.05
      Kidney biopsy data
      No. of glomeruli14NANA15NA
      No. of oxalate crystals43NANA28NA
      No. of glomerular abnormalities9 (82%)6 (50%)30 (59%)6 (29%)7 (28%)
      Outcome
      Follow-up duration, mo191813293
      Kidney failure8 (73%)3 (25%)30 (59%)11 (52%)6 (24%)
      Time to kidney failure, mo0.83NA0.2NA
      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.
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      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.
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      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.
      Approximately two-thirds of the patients have malabsorption-associated hyperoxaluria.
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      We found that chronic pancreatitis and gastric bypass were the most common causes of oxalate nephropathy (48%).
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      Of note, Lumlertgul et al
      • Lumlertgul N.
      • Siribamrungwong M.
      • Jaber B.L.
      • Susantitaphong P.
      Secondary oxalate nephropathy: a systematic review.
      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.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      This suggests that the combination of the hyperoxaluria-enabling condition with an additional factor or trigger may lead to crystal formation and kidney damage
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      ,
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Hermans M.P.
      • Jadoul M.
      • Demoulin N.
      Weight loss at a high cost: orlistat-induced late-onset severe kidney disease.
      ,
      • Borceux P.
      • Aydin S.
      • Demoulin N.
      • Devresse A.
      Acute renal failure and a “rejuvenating powder”.
      (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.
      • Nasr S.H.
      • D’Agati V.D.
      • Said S.M.
      • et al.
      Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      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.
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      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.
      • Glew R.H.
      • Sun Y.
      • Horowitz B.L.
      • et al.
      Nephropathy in dietary hyperoxaluria: a potentially preventable acute or chronic kidney disease.
      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.
      • Cossey L.N.
      • Dvanajscak Z.
      • Larsen C.P.
      A diagnostician field guide to crystalline nephropathies.
      Calcium oxalate crystals are strongly birefringent on polarized light, unlike calcium phosphate crystals
      • Demoulin N.
      • Jadoul M.
      • Cosyns J.P.
      • Labriola L.
      An easily overlooked iatrogenic cause of renal failure.
      (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.
      • Amin R.
      • Asplin J.
      • Jung D.
      • et al.
      Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria.
      ,
      • Nasr S.H.
      • D’Agati V.D.
      • Said S.M.
      • et al.
      Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure.
      ,
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      ,
      • Yang Y.
      • Shrame P.D.
      • Nair V.
      • et al.
      Kidney oxalate crystal deposition in adult patients: a relatively common finding.
      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.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      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.
      • Markowitz G.S.
      • Nasr S.H.
      • Klein P.
      • et al.
      Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing.
      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.
      • Mulay S.R.
      • Anders H.J.
      Crystal nephropathies: mechanisms of crystal-induced kidney injury.
      • Mulay S.R.
      • Evan A.
      • Anders H.J.
      Molecular mechanisms of crystal-related kidney inflammation and injury: implications for cholesterol embolism, crystalline nephropathies and kidney stone disease.
      • Mulay S.R.
      • Kulkarni O.P.
      • Rupanagudi K.V.
      • et al.
      Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion.
      • Knauf F.
      • Asplin J.R.
      • Granja I.
      • et al.
      NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy.
      In mice, Nlrp3 deletion successfully protects from progressive kidney failure secondary to ingestion of a diet high in soluble oxalate.
      • Knauf F.
      • Asplin J.R.
      • Granja I.
      • et al.
      NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy.
      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.
      • Anders H.J.
      • Suarez-Alvarez
      • Grigorescu M.
      • et al.
      The macrophage and inflammasome component NLRP3 contributes to nephrocalcinosis-related chronic kidney disease independent from IL-1-mediated tissue injury.
      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.
      • Mulay S.R.
      • Anders H.J.
      Crystal nephropathies: mechanisms of crystal-induced kidney injury.
      Crystal deposition is a potent driver of kidney fibrosis, leading to loss of kidney function.
      • Mulay S.R.
      • Anders H.J.
      Crystal nephropathies: mechanisms of crystal-induced kidney injury.
      ,
      • Mulay S.R.
      • Evan A.
      • Anders H.J.
      Molecular mechanisms of crystal-related kidney inflammation and injury: implications for cholesterol embolism, crystalline nephropathies and kidney stone disease.

      Hyperoxaluria and Progression of CKD

      Given the potential nephrotoxicity of oxalate at high levels, Waikar et al
      • Waikar S.S.
      • Srivastava A.
      • Palsson R.
      • et al.
      Association of urinary oxalate excretion with the risk of chronic kidney disease progression.
      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.
      • Waikar S.S.
      • Srivastava A.
      • Palsson R.
      • et al.
      Association of urinary oxalate excretion with the risk of chronic kidney disease progression.
      The association between hyperoxaluria and faster decline in eGFR was also shown in a small cohort of patients with chronic pancreatitis.
      • Demoulin N.
      • Issa Z.
      • Crott R.
      • et al.
      Enteric hyperoxaluria in chronic pancreatitis.
      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.
      • Bagnasco S.M.
      • Mohammed B.S.
      • Mani H.
      • et al.
      Oxalate deposits in biopsies from native and transplanted kidneys, and impact on graft function.
      ,
      • Pinheiro H.S.
      • Camara N.O.S.
      • Osaki K.S.
      • De Moura L.A.R.
      • Pacheco-Silva A.
      Early presence of calcium oxalate deposition in kidney graft biopsies is associated with poor long-term graft survival.
      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.
      • Efe O.
      • Verma A.
      • Walkar S.S.
      Urinary oxalate as a potential mediator of kidney disease in diabetes mellitus and obesity.
      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 intake
      • Robijn S.
      • Hoppe B.
      • Vervaet B.A.
      • D’Haese P.C.
      • Verhulst A.
      Hyperoxaluria: a gut-kidney axis?.
      ,
      • Witting C.
      • Langman C.B.
      • Assimos D.
      • et al.
      Pathophysiology and treatment of enteric hyperoxaluria.
      ,
      • Nazzal L.
      • Puri S.
      • Goldfarb D.S.
      Enteric hyperoxaluria: an important cause of end-stage kidney disease.
      (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.
      • Witting C.
      • Langman C.B.
      • Assimos D.
      • et al.
      Pathophysiology and treatment of enteric hyperoxaluria.
      Additionally, calcium supplements are given orally to reduce the bioavailability of intestinal oxalate and its absorption.
      • Witting C.
      • Langman C.B.
      • Assimos D.
      • et al.
      Pathophysiology and treatment of enteric hyperoxaluria.
      ,
      • Lindsjö M.
      • Fellström B.
      • Ljunghall S.
      • et al.
      Treatment of enteric hyperoxaluria with calcium-containing organic marine hydrocolloid.
      Crystallization inhibitors such as citrate may also be used.
      • Robertson W.G.
      Do “inhibitors of crystallization” play any role in the prevention of kidney stones? A critique.
      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.
      • Asplin J.R.
      The management of patients with enteric hyperoxaluria.
      Table 2Current and Potential Therapies of Secondary Hyperoxaluria
      TreatmentRationaleSupporting evidence
      High fluid intake (urine output >2-3 L/d)Reduces urine calcium oxalate supersaturation.Reduces stone formation.
      • Borghi L.
      • Guerra A.
      • Meschi T.
      • et al.
      Relationship between supersaturation and calcium oxalate crystallization in normal and idiopathic calcium oxalate stone formers.
      ,
      • Cheungpasitporn W.
      • Rossetti S.
      • Friend K.
      • Erickson S.T.
      • Lieske J.C.
      Treatment effect, adherence, and safety of high fluid intake for the prevention of incident and recurrent kidney stones: a systematic review and meta-analysis.
      Low-oxalate dietReduces 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.
      • Asplin J.R.
      The management of patients with enteric hyperoxaluria.
      ,
      • Holmes R.P.
      • Goodman H.O.
      • Assimos D.G.
      Contribution of dietary oxalate to urinary oxalate excretion.
      ,
      • Nordenvall B.
      • Backman L.
      • Burman P.
      • Larsson L.
      • Tiselius H.G.
      Low-oxalate, low-fat dietary regimen in hyperoxaluria following jejunoileal bypass.
      Low-fat dietReduces intestinal oxalate absorption (by increasing bioavailability of intestinal calcium).Reduces urinary oxalate excretion in small studies.
      • Nordenvall B.
      • Backman L.
      • Burman P.
      • Larsson L.
      • Tiselius H.G.
      Low-oxalate, low-fat dietary regimen in hyperoxaluria following jejunoileal bypass.
      ,
      • Andersson H.
      • Jagenburg R.
      Fat-reduced diet in the treatment of hyperoxaluria in patients with ileopathy.
      Normal-calcium dietAvoid low-calcium diets, which lead to more free intestinal oxalate.Reduces urinary oxalate excretion in small-sized studies.
      • Holmes R.P.
      • Goodman H.O.
      • Assimos D.G.
      Contribution of dietary oxalate to urinary oxalate excretion.
      ,
      • Penniston K.L.
      • Nakada S.Y.
      Effect of dietary changes on urinary oxalate excretion and calcium oxalate supersaturation in patients with hyperoxaluric stone formation.
      Calcium supplementsReduce bioavailability of intestinal oxalate and its absorption.Reduces urinary oxalate excretion but may lead to hypercalciuria.
      • Penniston K.L.
      • Nakada S.Y.
      Effect of dietary changes on urinary oxalate excretion and calcium oxalate supersaturation in patients with hyperoxaluric stone formation.
      • Stauffer J.Q.
      Hyperoxaluria and intestinal disease: the role of steatorrhea and dietary calcium in regulating intestinal oxalate absorption.
      • Barilla D.E.
      • Notz C.
      • Kennedy D.
      • Pak C.Y.
      Renal oxalate excretion following oral oxalate loads in patients with ileal disease and with renal and absorptive hypercalciurias: effect of calcium and magnesium.
      Calcium citrate may be more bioavailable than calcium carbonate.
      • Tondapu P.
      • Provost D.
      • Adams-Huet B.
      • Sims T.
      • Chang C.
      • Sakhaee K.
      Comparison of the absorption of calcium carbonate and calcium citrate after Roux-en-Y gastric bypass.
      CholestyramineBinds intestinal bile acids, reduces diarrhea, and binds oxalate in vitro.Studies show contradicting results.
      • Nordenvall B.
      • Backman L.
      • Burman P.
      • Larsson L.
      • Tiselius H.G.
      Low-oxalate, low-fat dietary regimen in hyperoxaluria following jejunoileal bypass.
      ,
      • Stauffer J.Q.
      Hyperoxaluria and intestinal disease: the role of steatorrhea and dietary calcium in regulating intestinal oxalate absorption.
      ,
      • Smith L.H.
      • Fromm H.
      • Hofmann A.F.
      Acquired hyperoxaluria, nephrolithiasis, and intestinal disease: description of a syndrome.
      Oxalobacter formigenes administrationIncreases intestinal oxalate degradation.Reduces urinary oxalate excretion in rat model
      • Canales B.K.
      • Hatch M.
      Oxalobacter formigenes colonization normalizes oxalate excretion in a gastric bypass model of hyperoxaluria.
      ,
      • Hatch M.
      • Cornelius J.
      • Allison M.
      • Sidhu H.
      • Peck A.
      • Freel R.W.
      Oxalobacter sp. reduces urinary oxalate excretion by promoting enteric oxalate secretion.
      and plasma oxalate levels in dialysis patients with primary hyperoxaluria (phase 2 study).
      • Hoppe B.
      • Pellikka P.A.
      • Dehmel B.
      • Banos A.
      • Lindner E.
      • Herberg U.
      Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria type 1 and end-stage renal disease: a phase II study.
      Oxalate decarboxylaseDegrades intestinal oxalate.Reduces urinary oxalate excretion in rat model
      • Grujic D.
      • Salido E.C.
      • Shenoy B.C.
      • et al.
      Hyperoxaluria is reduced and nephrocalcinosis prevented with an oxalate-degrading enzyme in mice with hyperoxaluria.
      and in phase 3 pilot study in humans.
      • Lingerman J.E.
      • Pareek G.
      • Easter L.
      • et al.
      ALLN-177, oral enzyme therapy for hyperoxaluria.
      NLRP3-specific inflammasome inhibitorReduces crystal-induced kidney damage.Reduces calcium-oxalate crystal-induced kidney fibrosis in mouse model.
      • Ludwig-Portugall I.
      • Bartok E.
      • Dhana E.
      • et al.
      A NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.
      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.
      • Canales B.K.
      • Hatch M.
      Oxalobacter formigenes colonization normalizes oxalate excretion in a gastric bypass model of hyperoxaluria.
      In humans, this strategy has only been tested in patients with primary hyperoxaluria.
      • Hoppe B.
      • Pellikka P.A.
      • Dehmel B.
      • Banos A.
      • Lindner E.
      • Herberg U.
      Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria type 1 and end-stage renal disease: a phase II study.
      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.
      • Lingerman J.E.
      • Pareek G.
      • Easter L.
      • et al.
      ALLN-177, oral enzyme therapy for hyperoxaluria.
      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.
      • Mulay S.R.
      • Anders H.J.
      Crystal nephropathies: mechanisms of crystal-induced kidney injury.
      As previously mentioned, a NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.
      • Ludwig-Portugall I.
      • Bartok E.
      • Dhana E.
      • et al.
      A NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.
      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.
      • Buysschaert B.
      • Aydin S.
      • Morelle J.
      • Gillion V.
      • Jadoul M.
      • Demoulin N.
      Etiologies, clinical features, and outcome of oxalate nephropathy.
      ,
      • Cartery C.
      • Faguer S.
      • Karras A.
      • et al.
      Oxalate nephropathy associated with chronic pancreatitis.
      ,
      • Cuvelier C.
      • Goffin E.
      • Cosyns J.P.
      • Wauthier M.
      • de Strihou C.
      Enteric hyperoxaluria: a hidden cause of early renal graft failure in two successive transplants: spontaneous late graft recovery.
      Morpho-constitutional analysis of kidney stones, combining stereomicroscopy and Fourier-transform infrared spectroscopy, may help in determining the cause of hyperoxaluria.
      • Corrales M.
      • Doizi S.
      • Barghouthy Y.
      • Traxer O.
      • Daudon M.
      Classification of stones according to Michel Daudon: a narrative review.
      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.
      • Asplin J.R.
      The management of patients with enteric hyperoxaluria.
      In patients with hyperoxaluria and/or oxalate nephropathy of unknown etiology, primary hyperoxaluria must not be overlooked (see the previous section).
      • Van der Hoeven S.M.
      • van Woerden C.S.
      • Groothoff J.W.
      Primary hyperoxaluria type 1, a too often missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort.
      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 Information

      Authors’ 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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