Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria is an inherited error of metabolism due to defective enzyme activity. In contrast, secondary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease. When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in various organ systems in a process called systemic oxalosis. Increased urinary oxalate levels help to make the diagnosis while plasma oxalate levels are likely to be more accurate when patients develop chronic kidney disease. Definitive diagnosis of primary hyperoxaluria is achieved by genetic studies and if genetic studies prove inconclusive, liver biopsy is undertaken to establish diagnosis. Diagnostic clues pointing towards secondary hyperoxaluria are a supportive dietary history and tests to detect increased intestinal absorption of oxalate. Conservative treatment for both types of hyperoxaluria includes vigorous hydration and crystallization inhibitors to decrease calcium oxalate precipitation. Pyridoxine is also found to be helpful in approximately 30% patients with primary hyperoxaluria type 1. Liver-kidney and isolated kidney transplantation are the treatment of choice in primary hyperoxaluria type 1 and type 2 respectively. Data is scarce on role of transplantation in primary hyperoxaluria type 3 where there are no reports of end stage renal disease so far. There are ongoing investigations into newer modalities of diagnosis and treatment of hyperoxaluria. Clinical differentiation between primary and secondary hyperoxaluria and further between the types of primary hyperoxaluria is very important because of implications in treatment and diagnosis. Hyperoxaluria continues to be a challenging disease and a high index of clinical suspicion is often the first step on the path to accurate diagnosis and management.

Oxalate is the ionic form of oxalic acid and is derived from various animal and plant sources. Oxalate is excreted mainly through the kidneys. Hyperoxaluria is a state of disordered metabolism characterized by an increased urinary excretion of oxalate. The normal daily oxalate excretion in healthy individuals ranges between 10-40 mg per 24 h. Concentrations exceeding 40-45 mg per 24 h are considered as clinical hyperoxaluria[1-3]. This may result from increased endogenous production of oxalate in primary hyperoxaluria (PH) or from increased intestinal absorption or increased intake of oxalate precursors in secondary hyperoxaluria (SH).

Hyperoxaluria has the potential to cause devastating consequences which can present as early as infancy or in the sixth decade of life and if not addressed appropriately, can cause significant morbidity and mortality including End Stage Renal Disease (ESRD)[4]. Elevated plasma oxalate levels lead to oxalate deposition in various organ systems. Systemic oxalosis should be prevented but the diagnosis is often delayed in more than 40% of patients. In a survey by Hoppe et al[5], 30% of the patients were diagnosed only when they had already reached ESRD. In some cases, the diagnosis may first be made when the disease recurs following renal transplant[6]. Hyperoxaluria continues to be a challenging disease and appropriate treatment requires a high index of suspicion and a timely diagnosis.

This review highlights the mechanisms underlying both primary and secondary hyperoxaluria, clinical manifestations, important elements in screening and diagnosis, and our current knowledge of modalities of treatment.

Oxalate is obtained from exogenous sources as well as endogenous synthesis. Oxalate is abundantly found in plant and animal sources. Dietary sources richest in oxalate include nuts, plums, chocolate, beetroot, strawberries, rhubarb, tofu and spinach[1,7]. Juicing is a recent popular trend where a diet based mainly on fruits and vegetable juices is consumed and may supply a very high amount of daily oxalate[8,9]. Studies have demonstrated that as the dietary intake of oxalate increases, so does the urinary concentration of oxalate[10]. Endogenous synthesis of oxalate occurs in the liver[11] through a pathway that generates glyoxalate as an intermediate molecule[12]. Glyoxalate is synthesized from oxidation of glycolate through enzymatic action of glycolate oxidase or from metabolism of hydroxyproline which is found in collagen or dietary sources. Increased glyoxalate is converted to oxalate by action of lactate dehydrogenase in the absence of enzymatic activity as is seen in the various types of PH[12,13]. This pathway is depicted in Figure 1.

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Figure 1 Pathway of oxalate synthesis and enzymatic defects in PH. A: PH1, alanine glyoxalate aminotransferase; B: PH 2, glycolate reductase hydroxy pyruvate reductase; C: PH 3, 4-hydroxy 2-ketoglutarate aldolase; D: Lactate dehydrogenase.

Renal oxalate handling comprises glomerular filtration, tubular secretion and tubular reabsorption[14,15]. Glomerular filtration depends on the plasma oxalate levels while tubular transport is mediated by SLC26 family of transport proteins. SLC26A1 mediates oxalate uptake into the cell across the basolateral membrane in exchange for sulfate[16,17]. On the apical side of the tubular cells, SLC26A6 is the dominant chloride-oxalate exchanger which promotes chloride reabsorption in exchange for oxalate secretion and has been implicated in the development of renal stones. This exchanger also mediates intestinal secretion of oxalate and loss of this exchanger has been shown to promote increased intestinal absorption of oxalate in the small intestine[18,19]. In rat kidney, tubular reabsorption has been demonstrated in the S1 and S2 segments of the proximal tubule[14] which may help decrease the tendency for calcium oxalate supersaturation in the earlier parts of the nephron[3].

Overall, the contribution of tubular secretion in addition to glomerular filtration is critical in regulating plasma oxalate levels as a strong correlation has been demonstrated between high plasma oxalate levels and oxalate secretion[20]. It has also been noted that tubular oxalate secretion is increased in PH patients possibly in an attempt to mitigate the life threatening consequences of systemic oxalosis[21]. Increased tubular secretion has also been noted in patients with hyperoxaluria following intestinal bypass[22].

The causes of SH are increase in dietary and intestinal absorption (enteric hyperoxaluria), excessive intake of oxalate precursors and alteration in intestinal microflora.

The prevalence of PH1 is approximately 1-3 cases per million population[46,47]. At least 1% of the ESRD seen in the pediatric population is attributable to PH1 in European and Japanese studies[48,49]. It is more frequently seen in Kuwaiti and Tunisian populations where consanguineous marriages are practiced[50,51]. PH1 is the most severe type of PH although there is significant variability in its clinical presentation. Patients may present early in life during infancy with life threatening oxalosis and failure to thrive or in adulthood after passing an occasional stone. Overall, the disease is characterized by recurrent nephrolithiasis and progressive nephrocalcinosis leading to renal damage and as a result, the majority of the patients reach ESRD during 3^rd-5^th decade of life[52,53].

PH2 is a less aggressive form of PH with better preservation of renal function and lower incidence of end stage renal disease and less severe nephrocalcinosis compared to PH1. The differences are accounted for by the higher oxalate excretion in PH1 and altered urine composition with reduced urinary levels of citrate and magnesium in PH1 compared to PH2[54].

PH3 generally presents with recurrent nephrolithiasis in the early decades of life. It is also characterized by the increase in urinary calcium levels and genetic defects in the HOGA1 gene have also been implicated in cases of idiopathic calcium oxalate urolithiasis[55]. The disease course is more benign compared to other forms and although limited clinical data is available, no cases of ESRD have been reported to date with PH3[56,57].

Patients with secondary hyperoxaluria have a predisposition to developing recurrent calcium oxalate stones due to the underlying disorder. This leads to worsening renal damage and progression to ESRD. Systemic oxalosis is less common in secondary hyperoxaluria but reported in some severe cases of Crohn’s disease[58].

Calcium oxalate salts are poorly soluble in body fluids. Calcium oxalate deposits within renal tissue as nephrocalcinosis and also forms renal stones (nephrolithiasis). This leads to progressive renal injury and inflammation and tubular obstruction leading to interstitial fibrosis, declining renal function and eventually ESRD[52,59].

When glomerular filtration rate (GFR) drops below 30-40 mL/min per 1.73 m², renal capacity to excrete calcium oxalate is significantly impaired. At this stage, calcium oxalate starts to deposit in extra renal tissues in a process called systemic oxalosis. Calcium oxalate deposits have been reported in the myocardium, cardiac conduction system, kidneys, bones and bone marrow. This leads to cardiomyopathy, heart block and other cardiac conduction defects, vascular disease, retinopathy, synovitis, oxalate osteopathy and anemia that is noted to be resistant to treatment[52,60,61].

Screening for hyperoxaluria must be undertaken in every child with the first episode of renal stone and all adults who present with recurrent calcium oxalate stones. Screening should also be done at first presentation of nephrocalcinosis or family history of stone disease at any age. Furthermore, screening must be offered to relatives of an index case. PH1 should be strongly considered in the differential in any patient with renal failure of unknown etiology, particularly when there is nephrocalcinosis with reduced renal function or a high occurrence of renal stones. Presence of monohydrate calcium oxalate crystals in biological fluids or tissues is also a strong pointer towards primary hyperoxaluria and should be followed up with additional testing[62].

Diagnosis of hyperoxaluria is established using a combination of clinical, radiological, biochemical, histopathological and genetic studies in primary hyperoxaluria. Precise diagnosis is of paramount importance for prognostic and treatment implications and also for prenatal screening in appropriate cases where PH is suspected.

In patients with a clinical suspicion for hyperoxaluria, the diagnostic workup should begin with ultrasound or other radiological imaging of the kidneys and the rest of the urinary tract to confirm the presence of nephrocalcinosis and urolithiasis[2,53]. Stone analysis should be done and may yield the initial diagnostic clues for PH. Stones in PH are composed of monohydrate calcium oxalate (whewellite) which assume a dumbbell shaped form[63].

The initial biochemical tests include urinary oxalate excretion preferably measured in 24 h urine collection and adjustment of the oxalate excretion per 1.73 m² of the body surface area is recommended[2]. Urinary oxalate: urinary creatinine ratios can be used but age specific normal values must be known. These values however should be interpreted with caution as the ratios decline in early life and are also subject to variability based on nutritional intake. Oxaluria must be confirmed using two urine samples. PH is characterized by urinary oxalate excretion > 1.0 mmol/1.73 m² per 24 h in majority and in some cases may exceed 2.0 mmol/1.73 m²/ 24 h in contrast to the normal urinary excretion which is typically < 0.45 mmol/1.73 m² per 24 h. In patients with hyperoxaluria > 0.8 mmol/1.73 m² per 24 h, urinary glycolate and glycerate levels should be measured. About two thirds of PH1 patients have elevated urinary glycolate levels but it is important to remember that normal glycolate levels do not exclude the diagnosis. Urinary glycerate levels are noted to be high in PH2 patients[2,53].

As GFR declines, urinary excretion of oxalate decreases and the urinary oxalate estimation may no longer be accurate. Plasma oxalate should be measured in these circumstances. In PH patients with ESRD, plasma oxalate levels are typically higher than 80 μmol/L while in non PH hyperoxaluric patients, the plasma oxalate level may range between 30-80 μmol/L[64-66]. This is in contrast to plasma oxalate levels of 1-5 μmol/L in normal subjects[1].

Non-invasive, definitive diagnosis of PH is provided by testing of AGXT, GRHPR and HOGA1 genes. There are 150 known mutations for AGXT[67], 16 for GRHP[26] and 15 for HOGA1[28,55-57,68]. Williams et al[69] showed that targeted analysis of the three most common mutations in AGXT (c.33_34insC, c.508G>A, and c.731T>C) provides the diagnosis in 34.5% PH1 patients while exon sequencing of exon 1, 4 and 7 increases the yield and allows diagnosis in 50% PH1 patients. Prenatal diagnosis can be done by testing chorionic villi. In patients with one or no known mutation, intragenic and extragenic linkage analysis is recommended for diagnosis[70,71] .When DNA screening is non diagnostic but clinical suspicion is high, liver biopsy is undertaken for establishing the diagnosis. However, this is an invasive method and carries a high risk of complications like bleeding[53].

In SH, stones are usually mixed (whewellite and weddellite) in contrast to PH. The excretion of urinary oxalate is increased in SH and may be > 0.7 mmol/1.73 m² per 24 h but in some cases may exceed 1.0 mmol/1.73 m² per 24 h[2,72,73]. Other available diagnostic tests include use of PCR in stool samples to identify oxalobacter formigenes[74,75]. Also, Increased intestinal oxalate absorption can be assessed by an absorption test using (¹³C2) oxalate[76]. This test can help identify hyperabsorbers who would benefit from dietary interventions focusing on lowering oxalate and increasing calcium in the diet. This diagnostic test also helps to differentiate between primary and secondary forms of hyperoxaluria[33].

Radiological imaging may aid in diagnosis of multisystem involvement. Renal involvement, apart from urolithiasis, may show two distinct patterns: medullary nephrocalcinosis which is evaluated well on ultrasound while CT scan is a better modality for diagnosis of cortical nephrocalcinosis. CT may also be helpful in detection of calcium oxalate deposition in various other organ systems like bowel wall, muscle and arteries. The effects on the heart can be evaluated by electrocardiography and echocardiography. Skin biopsy may be necessary for skin lesions secondary to calcium oxalate deposition which can resemble the lesions of calciphylaxis[62]. On histopathological examination, calcium oxalate crystals demonstrate a characteristic birefringence when examined under polarized light. Figures 2 and 3 demonstrate calcium oxalate deposition in renal tissue.

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Figure 2 Calcium oxalate deposition in the renal tubules (black arrows).

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Figure 3 Examination of renal biopsy specimen under polarized light. Calcium oxalate crystals depict a characteristic birefringence.