Update on Oxalate Crystal Disease

Abstract

Oxalate arthropathy is a rare cause of arthritis characterized by deposition of calcium oxalate crystals within synovial fluid. This condition typically occurs in patients with underlying primary or secondary hyperoxaluria. Primary hyperoxaluria constitutes a group of genetic disorders resulting in endogenous overproduction of oxalate, whereas secondary hyperoxaluria results from gastrointestinal disorders associated with fat malabsorption and increased absorption of dietary oxalate. In both conditions oxalate crystals can deposit in the kidney leading to renal failure. Since oxalate is primarily renally eliminated, it accumulates throughout the body in renal failure, a state termed oxalosis. Affected organs can include bones, joints, heart, eyes and skin. Since patients can present with renal failure and oxalosis before the underlying diagnosis of hyperoxaluria has been made, it is important to consider hyperoxaluria in patients who present with unexplained soft tissue crystal deposition. The best treatment of oxalosis is prevention. If patients present with advanced disease, treatment of oxalate arthritis consists of symptom management and control of the underlying disease process.

Introduction

Oxalate arthritis is an uncommon cause of arthropathy, typically seen in patients with hyperoxaluria. Oxalate (C₂O₄²⁻) is an organic compound that can be generated endogenously via metabolism, or incorporated exogenously via the diet. Endogenous overproduction occurs in genetic disorders referred to as the primary hyperoxalurias (PH). A variety of gastrointestinal diseases associated with fat malabsorption result in secondary hyperabsorption of oxalate from the gut. Occasionally, oral intake of foods very high in oxalate or intake of precursors of oxalate may result in a substantial oxalate load. Regardless of its source, oxalate cannot be metabolized and must be excreted in the urine. Over time, excessive urinary oxalate can damage the kidneys leading to reduced renal excretion. Once the glomerular filtration rate declines to less than 30–40 ml/min/1.73m², renal excretion cannot fully eliminate the oxalate load and plasma levels increase rapidly ¹. When the plasma calcium oxalate supersaturation level exceeds the point of spontaneous crystallization, calcium oxalate begins to deposit throughout the body, a condition called oxalosis ¹.

In patients with oxalosis, calcium oxalate crystals may deposit within the synovial space causing arthritis. Oxalate arthritis is often difficult to distinguish from other causes of crystalline arthritis, and identification of calcium oxalate crystals within the synovial fluid is required for diagnosis. Importantly, patients can present with renal failure and oxalosis before a diagnosis of hyperoxaluria has been made. Therefore, it is important to consider hyperoxaluria in patients who present with unexplained soft tissue crystal deposition, including crystalline arthritis. The purpose of this article is to review the pathophysiology, manifestations and treatment of oxalate disorders, with a focus on oxalate arthritis.

Primary Hyperoxaluria

The primary hyperoxalurias are a group of rare autosomal recessive, inherited diseases with an estimated prevalence of less than 3 in one million and an incidence of 0.15 × 10⁶/year ². Three types of PH have been characterized (PH1, PH2, PH3). In all three types, glyoxylate is aberrantly metabolized into oxalate. A remaining subgroup of patients exists that appear to have a genetic cause of hyperoxaluria that cannot be classified into one of the 3 known types.

PH1 is the most common form of PH and accounts for 70–80% of all cases ¹. It is caused by mutations in the AGXT gene that encodes the liver-specific peroxisomal enzyme alanine/glyoxylate aminotransferase (AGT). The AGT protein is responsible for converting glyoxylate into glycine within liver peroxisomes. Over 100 disease-causing mutations in AGXT have been reported ¹. PH1 is the most severe form of the disease, and typically manifests in childhood with recurrent kidney stones and nephrocalcinosis. ESRD often develops by age 40–50 years but can occur at any age, including infancy ³.

Primary hyperoxaluria type 2 (PH2) is less common than PH1 and accounts for approximately 10% of cases. It is caused by mutations in the GRHPR gene leading to dysfunction of the enzyme glyoxylate/hydroxypyruvate reductase (GR/HPR), another enzyme that metabolizes glyoxalate. In the setting of decreased enzyme activity, glyoxylate is aberrantly converted into oxalate. Unlike AGT, GR/HPR is not limited to the liver and is expressed throughout the body. Patients with PH2 tend to have lower urinary oxalate levels and better renal outcomes than patients with PH1 ⁴.

The enzyme pathway involved in PH3 has been elucidated only recently. PH3 is caused by mutations in the HOGA1 gene that reduce function of the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA1) ⁵. It is known that the HOGA1 protein is involved in hydroxyproline metabolism, but exactly how these mutations result in hyperoxaluria is not completely clear. Altered conversion of hydroxyproline to glyoxylate that in turn leads to overproduction of oxalate has been suggested ^{6, 7}. Patients with PH3 appear to be less likely to develop end-stage renal disease than patients with the other two types of PH ³.

Secondary hyperoxaluria

Secondary hyperoxaluria results from increased intestinal absorption of dietary oxalate, also referred to as enteric hyperoxaluria. Foods rich in oxalate include spinach, rhubarb, sweet potatoes and peanuts. Normally, oxalate within food is complexed with calcium rendering it difficult to absorb. In states of fat malabsorption, however, free fats in the colonic lumen bind calcium (saponification), thereby increasing the amount of free oxalate available for absorption ^8–10. Free fats and possibly bile acids may also increase colonic oxalate permeability ¹¹. In patients with fat malabsorption and an intact colon, oxalate absorption can increase dramatically from the normal level of 5–10% to over 30% ¹². Enteric hyperoxaluria is associated with a diverse number of conditions that cause fat malabsorption, including inflammatory bowel disease ¹³, celiac disease ¹⁴, short bowel syndrome, chronic pancreatitis ¹⁵, biliary cirrhosis ¹⁶ and bariatric surgery ^{10, 17, 18}. Forms of malabsorptive bariatric surgery including Roux-en-Y gastric bypass and jejunoileal bypass are associated with enteric hyperoxaluria ¹⁹, but not restrictive procedures such as gastric banding ²⁰. Rates of hyperoxaluria following malabsorptive gastric bypass procedures are estimated to be 20–29% ^{21, 22}. The hyperoxaluria can be severe and can result in kidney failure. In selected older case reports, oxalate nephropathy stabilized or improved after reversal of jejunoileal bypass surgery ^{23, 24}. Oxalate hyperabsorption can also result from medications such as orlistat that interfere with fat absorption from the gastrointestinal tract ²⁵. Although cases of hyperoxaluria associated with this medication are typically milder, acute kidney injury associated with calcium oxalate crystal deposition has been described ²⁶

In all cases of enteric hyperoxaluria, an intact colon is necessary for enteric hyperoxaluria to develop ¹². Colonic oxalate absorption is thought to be largely passive and paracellular ²⁷. Recently, however, it has been demonstrated that the apical SLC26A6 anion transporter can actively secrete oxalate, and that SLC26A6 knockout animals become hyperoxaluric. This colonic secretory mechanism may be under hormonal influences ^{28, 29}, although methods to manipulate it for therapeutic effect have not yet been discovered.

Ethylene glycol is hepatically-metabolized to oxalate, hence acute kidney injury is a well-known complication of ethylene glycol poisoning ³⁰. If cases are diagnosed early enough, fomeprazole can be administered to inhibit the conversion of ethylene glycol to oxalate by alcohol dehydrogenase ³¹. Rarely, ingestion of large amounts of oxalate-rich foods such as rhubarb, star fruit or sorrel soup have been associated with acute kidney injury due to calcium oxalate crystal deposition ^{32, 33}.

Cellular reactions to oxalate crystals

Cell culture experiments suggest that once adherent to cells, calcium oxalate crystals set into motion a cascade of responses that include crystal internalization ^{34, 35}, changes in gene expression ³⁶, cytoskeletal reorganization ³⁴, and possibly cell proliferation ³⁷. Exposure of renal cells to calcium oxalate crystals stimulates expression of early response genes associated with mitogenesis and enhances expression of regulators of the extracellular matrix composition and specific growth factors which augment kidney fibroblast proliferation ³⁷. In addition, exposure of cultured renal cells to calcium oxalate crystals stimulates expression of the gene encoding osteopontin and release of this protein into the medium ³⁸. Importantly, many responses of cultured renal cells to calcium oxalate crystals replicate those initially reported in hyperoxaluric rats, including rapid adhesion of crystals to cells followed by internalization ^{34, 39–41}. Observations in renal tissue from hyperoxaluric subjects suggest similar processes occur in human kidneys in vivo ⁴².

Signs and symptoms

Patients with oxalate disorders display a variety of signs and symptoms. Oxalate is primarily eliminated via renal glomerular filtration. Given their direct role in oxalate excretion, the kidneys often sustain the most severe damage in states of oxalate excess. When increased quantities of oxalate are present in tubular fluid the anion can form insoluble complexes with calcium. Typically the supersaturation for calcium oxalate is not reached until the distal nephron, but in hyperoxaluric states crystallization can occur even in the proximal tubule. The resulting calcium oxalate crystals can damage tubular cells and also deposit within the renal parenchyma, pathologically referred to as nephrocalcinosis. Local inflammation and fibrosis can be the end result. Calcium oxalate crystals can also contribute to kidney stone formation and tubular obstruction. Patients with kidney stones frequently present with flank pain, hematuria or dysuria.

If renal function declines in patients with disorders of oxalate metabolism, calcium oxalate crystal deposition can occur within a variety of tissues (Table 1). Oxalate arthropathy, a rare cause of arthritis, is one manifestation of the resulting oxalosis ⁴³. Oxalate arthritis can be clinically indistinguishable from other crystal-induced arthropathies involving calcium phosphate, hydroxyapatite, calcium pyrophosphate dihydrate (CPPD) and monosodium urate. Oxalate arthritis may result from deposition of calcium oxalate crystals within bones, tendons, cartilage, and synovium. From these sites the crystals are thought to gain entry into the synovial fluid where they invoke an inflammatory response ⁴⁴ causing joint effusions and arthralgias ^{45, 46}. Alternatively, supersaturation of calcium oxalate within the synovial fluid itself may lead to local crystal formation, especially when fluid is removed during dialysis, a phenomenon referred to as articular hyperconcentration ⁴⁷. In general, oxalate arthritis is symmetric and polyarticular. It can be acute or chronic. Typical joint involvement includes the proximal interphalangeal and metacarpophalangeal joints, knees, elbows and ankles ⁴⁸. X-rays of the joints in hyperoxaluria may reveal calcification around the joints and within tendon sheaths and soft tissue ⁴⁵. Chondrocalcinosis of the metacarpophalangeal and metatarsophalangeal joints may be seen ⁴⁸. Spinal stenosis caused by oxalate crystal deposition within the ligamentum flavum has also been reported. Oxalate deposition can also result in synovitis, tenosynovitis and bursitis ⁴⁸.

Table 1.

Systemic manifestations of oxalate disorders

Organ	Manifestations
Joints	Arthritis Chondrocalcinosis of the metacarpophalangeal and metatarsophalangeal joints Spinal stenosis Synovitis Tenosynovitis Bursitis
Kidneys	Acute tubular necrosis Interstitial fibrosis Nephrocalcinosis Kidney stones
Heart	Arrhythmias Diastolic dysfunction Valvular abnormalities Impaired ejection fraction Infiltrative process
Skin	Livido reticularis Acrocyanosis Papules and nodules on face and digits Non-healing ulcers
Eyes	Retinal oxalate deposition
Nerve and muscle	Axon loss and demyelination Myopathies Polyradiculoneuropathies
Teeth	Peridontitis Jaw bone and root resorption Dental mobility
Bone marrow	Erythropoietin stimulating agent resistant anemia
Bones	Fractures Pseudofractures Sclerosis Cystic bone changes Dense metaphyseal bands Increased bone density

Bone involvement in hyperoxaluria can manifest as diffuse bone pain. X-ray imaging reveals fractures, pseudofractures ⁴⁵, sclerosis, cystic bone changes, subperiosteal resorption adjacent to oxalate deposits ^{48, 49}, dense metaphyseal bands ⁵⁰ and increased bone density ⁵¹ (see Figure 1). Calcium oxalate has a tendency to crystallize in previously damaged joints, such as distal and proximal interphalangeal joints involved in osteoarthritis, thus presenting as soft tissue calcification about the degenerated joint ⁴⁷. Inflammation may mimic the findings of erosive osteoarthritis or an atypical diuretic-related gout. High-resolution computed tomography (CT) may reveal advanced skeletal age, decreased bone mineral density, and altered bone microarchitecture ⁴⁹. Bone biopsy demonstrates oxalate crystals with surrounding granulomas containing histiocytes and macrophages with associated fibrosis ⁵². Patients with oxalosis and bone marrow involvement often develop anemia that is resistant to erythropoietin-stimulating agents ^{53, 54}.

Figure 1. Oxalate osteopathy.

Fracture deformities of both the proximal and distal tibia and fibula (arrows) in a 23-month-old girl with end stage renal failure secondary to type 1 PH.

Patients with cardiac involvement may present with arrhythmias due to crystal deposition within the conduction system. They may also present with palpitations, syncope, dyspnea and rarely chest pain ⁵⁵. Cardiac imaging may reveal valvular abnormalities ⁵⁶ and evidence of an infiltrative process with impaired right and left ejection fraction ⁵⁵. Skin manifestations in hyperoxaluria vary depending on whether the patient has primary or secondary hyperoxaluria. PH has been reported to cause cutaneous disease through deposition of oxalate within the vessels resulting in gangrene, livido reticularis and acrocyanosis. Secondary hyperoxaluria typically causes a milder cutaneous disease via extravascular oxalate deposition. Papules and nodules on the face and digits can be observed ⁵⁷. Oxalate crystal deposition within the retina is often observed and can cause visual disturbances in both primary and secondary hyperoxaluria ^58–60. Deposition within nerves and muscles can cause painful myopathies and progressive polyradiculoneuropathy. Biopsies of peripheral nerves reveal crystal deposition within axons and epineural blood vessels with associated axon loss and demyelination ^61–64. Oxalosis may also involve teeth ^65–67 and blood vessels of the heart and liver ^{68, 69}.

Diagnosis

The diagnosis of oxalate arthritis requires arthrocentesis and synovial fluid analysis ⁴⁵. Examination of synovial fluid reveals clear or cloudy fluid with a low cell count and calcium oxalate crystals ⁴⁸. Calcium oxalate crystals occur in two forms: monohydrate and dihydrate. Calcium oxalate monohydrate crystals appear as irregular squares or rods which may be confused with calcium pyrophosphate (CPP) crystals ⁴⁵. In contrast, calcium oxalate dihydrate crystals have a classic envelope-like shape and are more common ⁴⁷. Both types of oxalate crystals exhibit variable positive birefringence under polarized light, similar to CPP. The crystals also stain positive with alizarin red, indicating the presence of calcium ⁴⁵. Crystals may be intracellular or extracellular ⁴⁷. Radiographic imaging is unable to distinguish oxalate arthritis from other forms of arthritis such as CPP deposition (CPPD) ⁴⁵. Both may show chondrocalcinosis of the metacarpophalangeal or metatarsophalangeal joints on x-ray or CT imaging ⁴⁵. Occasionally, patients on chronic hemodialysis may have calcium oxalate crystals identified within synovial fluid without clinical or radiographic evidence of arthritis ⁴⁷. These patients do not have oxalate arthritis.

Any patient with systemic oxalosis, including oxalate arthritis, should be evaluated for an underlying oxalate disorder. If renal function is preserved (GFR> 40 ml/min/1.73m²) hyperoxaluria will be present, defined as a urinary oxalate level >0.5 mmol/1.73m² per 24 hr. Patients with PH and intact renal function have only mild increases in plasma oxalate levels. If renal function declines below 40 ml/min/1.73 m², however, plasma oxalate levels rise, urinary oxalate levels fall, and diagnosis can become more difficult ¹. In patients with chronic kidney disease (GFR <30ml/min/1.732m²), plasma oxalate values up to 30 µM/L can be normal. However, higher values strongly suggest the diagnosis of PH ⁷⁰.

In patients on dialysis the diagnosis of PH can be particularly challenging. Marked increases in plasma oxalate and/or increased plasma glycolate (PH1) or glycerate (PH2) can be helpful. Ultimately, the diagnosis of PH can be confirmed by genetic testing performed at specialized centers for common mutations involving AGXT, GRHPR and HOGA1. In cases where a high degree of clinical suspicion for PH exists, but genetic testing is unrevealing, a liver biopsy can be obtained to check AGT and GR/HPR enzymatic activities.

Secondary causes of hyperoxaluria should be considered in patients with gastrointestinal conditions associated with fat malabsorption. Examples include small intestinal resection, bariatric surgical procedures for obesity , chronic pancreatitis, and inflammatory bowel disease ^{71, 72–74}. Fecal fat determination remains the gold standard to document the presence of fat malabsorption.

Treatment

Symptomatic treatment of oxalate arthritis includes NSAIDs, colchicine and steroids. The use of these agents may be limited by side effects. NSAIDs should be avoided in patients with chronic kidney disease, including recipients of kidney transplants, because they may contribute to worsening renal function and hypertension. Side effects of colchicine include cytopenias, gastrointestinal toxicity, neuropathy and myopathy. Colchicine should be used sparingly or completely avoided in patients with chronic kidney disease. In addition, colchicine may interact with immunosuppressants such as cyclosporine or tacrolimus. Therefore intraarticular or oral steroids may be the safest treatment for patients with oxalate arthritis ⁴⁵. Calcium oxalate crystals induce inflammation via the NLRP3-IL-1β pathway ⁷⁵. In the future, IL-1β inhibitor therapies may play a therapeutic role in calcium oxalate disease.

The best treatment for oxalosis is prevention. Therefore, therapy for oxalate arthritis should focus on the underlying disease process. In general, patients with these rare disorders will benefit from consultation with a specialist familiar with these disease processes. If renal function is preserved, a guiding principle is that patients with either primary or secondary hyperoxaluria benefit from efforts to decrease oxalate precipitation in body tissues or in the urine. Hyperoxaluria can be addressed with hydration and crystalline inhibitors (Table 2). Patients with hyperoxaluria should drink at least 3 L of fluid per day in order to reduce the incidence of oxalate supersaturation in the urine. In addition, use of crystallization inhibitors such as oral phosphorus and citrate salts should be considered.

Table 2.

Treatment of hyperoxaluria

Treatment	Type of hyperoxaluria
Fluid intake > 3 L per day	All types, when renal function is preserved
Urinary crystal inhibitors Citrate Phosphorus Magnesium	PH with preserved renal function
Calcium supplementation with meals	Secondary hyperoxaluria due to fat malabsorption
Lanthanum supplementation	Possibly effective in secondary hyperoxaluria
Low-fat, low-oxalate diet	Secondary hyperoxaluria
Intensive hemodialysis	All types
Combined liver kidney transplantation	Type 1 PH
Kidney transplantation alone	Patients with type I PH and complete pyridoxine responsiveness Type 2 PH

Additional treatments for oxalate disorders depend on whether the underlying cause is primary or secondary. Patents with enteric hyperoxaluria benefit from adhering to a low-fat and low-oxalate diet. Patients with fat malabsorption are often prescribed calcium supplements with meals to promote binding of dietary oxalate and decreased intestinal absorption ¹⁹. Patients with fat malabsorption secondary to pancreatic insufficiency should benefit from pancreatic enzyme supplementation ⁷⁶. Recent studies suggest a promising role of the phosphate binder lanthanum carbonate in cases of secondary hyperoxaluria ⁷⁷. Lanthanum carbonate has been shown to inhibit intestinal oxalate absorption and prevent nephrocalcinosis in animal models ⁷⁷. Another commonly used phosphate binder, sevelamer hydrochloride, is less effective at binding oxalate ⁷⁸. Studies involving the use of probiotics in patients with enteric hyperoxaluria have demonstrated mixed results ^{79, 80}.

In contrast to patients with secondary hyperoxaluria, patients with PH benefit from targeted strategies to reduce endogenous oxalate production. PH1 patients should receive a trial of pyridoxine, or vitamin B6, supplementation. Pyridoxine serves as a cofactor for the deficient enzyme AGT. Pharmacologic doses of pyridoxine (5–9 mg/kg) have been shown to decrease urinary oxalate in approximately 30% of patients with PH1 ^{81, 82}. Patients with a specific genetic mutation [c.508G>A (G170R)] that results in mis-targeting of AGT to mitochondria instead of peroxisomes are most likely to respond to pyridoxine therapy ^{83, 84}.

In patients with PH in whom the glomerular filtration rate falls to < 30 ml/min/m², renal excretion is unable to keep pace with daily oxalate production. Dialysis is needed to augment oxalate removal and limit the development of progressive oxalosis ⁸⁵. The use of high flux dialyzers and daily dialysis is often required to remove as much oxalate as possible. Peritoneal dialysis alone is usually insufficient ⁸⁵. The use of continuous hemodialysis may be warranted in cases of severe systemic oxalosis ^{3, 86, 87}. In all cases, careful monitoring of plasma oxalate levels and dialysis oxalate removal is crucial.

Given that oxalate removal with dialysis is incomplete and consequences of progressive systemic oxalosis are severe, the preferred treatment for patients with PH is transplantation. Ideally, kidney transplantation should be performed prior to the initiation of dialysis, in order minimize oxalosis. Patients with PH can receive either a kidney transplant alone, or a combined liver/kidney transplant. PH1 patients with complete pyridoxine responsiveness may do well with kidney transplantation alone ^{3, 88, 89} with strict maintenance of pyridoxine therapy posttransplant. The remaining patients with PH1 should receive combined liver/kidney transplantation ⁹⁰. Liver transplantation successfully restores the hepatic enzyme deficiency and protects the renal allograft from the development of recurrent oxalate nephropathy. Following combined liver/kidney transplantation, renal allograft survival at three years has steadily improved over the past decade to 84% ^{43, 91, 92}. Even after a successful liver/kidney transplant, urinary oxalate excretion can remain elevated for months to years depending on the amount of oxalate that accumulated in the tissues prior to transplant. In contrast to PH1, the defective enzyme in PH2 is not liver-specific. To date there has been no confirmation that liver transplantation fully corrects GR/HPR enzyme deficiency in patients with PH2. In addition, the renal effects of PH2 are less severe than PH1. For these reasons, most PH2 patients receive a kidney transplant only ⁹¹.

New treatment strategies for hyperoxaluria are being evaluated. One active area of investigation focuses on the use of oral Oxalobacter formigenes, a Gram-negative, anaerobic intestinal bacteria that is often present in the human colon and is capable of oxalate degradation. Animal studies have suggested that endogenously generated oxalate can be eliminated in the intestinal tract via administration of this organism ^{27, 28, 93–95}. In humans, repeated antibiotic use can eliminate the bacteria from the intestine, and limited evidence suggests colonization correlates with urinary oxalate excretion ⁹⁶. Potentially, oral administration of O. formigenes could be a therapy for hyperoxaluria, particularly in patients whose endogenous microbiome lacksthe organism. However, animal studies ⁹⁷ and small pilot studies in humans have shown mixed results ^{98, 99}. Gene transfer therapy ¹⁰⁰ and the use of molecular chaperones to stabilize defective enzymes in PH are currently under investigation ^{101, 102}

Conclusions

Oxalate arthritis is a rare cause of arthritis which is clinically indistinguishable from other crystalline arthropathies. Oxalate arthritis must be diagnosed by synovial fluid analysis and demonstration of oxalate crystals within the joint fluid. Patients with oxalate arthritis should be evaluated for underlying oxalate disorders, given that this type of arthropathy is only seen in the setting of systemic oxalosis. In the presence of preserved kidney function, a 24-hour urine collection to detect hyperoxaluria is most helpful. Once GFR falls below 40 ml/min/1.73m², however, the diagnosis of PH becomes more difficult and genetic testing may be necessary. Secondary hyperoxaluria should be considered in patients with clinical conditions that can cause fat malabsorption. Patients with either primary or secondary hyperoxaluria are prescribed a large fluid intake and inhibitors of urinary crystallization. Targeted therapies for PH include pyridoxine, kidney transplantation, and in select cases (PH1) combined liver/kidney transplantation. Specific treatment strategies for secondary hyperoxaluria include a low-oxalate diet and calcium supplementation with meals. Studies investigating the role of novel therapeutic agents in the treatment of hyperoxaluria are ongoing.