INTRODUCTION — Primary hyperoxalurias (PHs) are rare inborn errors of glyoxylate metabolism characterized by the overproduction of oxalate, which is poorly soluble and is deposited as calcium oxalate in various organs. In patients with PH, the increased production results in increased urinary excretion of oxalate leading to kidney injury and, in some cases, end-stage kidney failure. The clinical manifestations, diagnosis, and treatment of PH are reviewed here.
GENETICS AND PATHOGENESIS
Genetics — Primary hyperoxaluria (PH) is primarily caused by autosomal recessive variants in three genes that encode enzymes involved in glyoxylate metabolism. These pathologic variants result in enhanced oxalate production (figure 1). As oxalate is typically excreted in the urine, the kidney is the prime target for excessive oxalate deposition resulting in nephrocalcinosis and kidney stones and, in some cases, end-stage kidney disease (ESKD).
●PH type 1 (MIM #259900) is due to variants of AGXT that encodes the hepatic peroxisomal enzyme alanine glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate-dependent enzyme, which is involved in the transamination of glyoxylate to glycine . This inborn error of metabolism leads to an increase in the glyoxylate pool, which is converted by lactate dehydrogenase to oxalate. It is the most common PH type and accounts for approximately 70 to 80 percent of PH cases [2,3]. It is the most severe form of PH, with more rapid progression to kidney dysfunction and the development of ESKD in one-half of patients by young adulthood, historically . (See 'Primary hyperoxaluria type 1' below.)
The AGXT gene maps to chromosome 2q36-37 and encodes for a 43 kDa protein [5,6]. More than 190 variants have been identified in the AGXT gene, which are found in all 11 exons of the gene [7-10]. The variants, most of which lead to a major or complete loss of enzyme activity, are predominantly single nucleotide substitutions (75 percent) including missense, nonsense, and splice site mutations, and the remaining variants are due to deletions and insertions [9,11].
These genetic variants result in three different expressions of AGT protein and its activity :
•Absence of both immunoreactive AGT protein and AGT catalytic activity, which occurs in approximately 40 percent of patients.
•Presence of immunoreactive AGT protein and absence of AGT catalytic activity, which occurs in approximately 15 percent of patients.
•Presence of both immunoreactive AGT protein and AGT catalytic activity, but at levels that are 50 percent below normal values. In these patients, most of the AGT is localized in the mitochondria and not in the peroxisomes (mistargeting phenotype). Four mutations (Gly170Arg, Ile244Thr, Phe152Ile, and Gly41Arg) result in both expression of AGT protein and activity.
●PH type 2 (MIM #260000) is due to variants of GRHPR that encodes the cytosolic enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which normally converts glyoxylate to glycolate . It accounts for approximately 10 percent of PH cases [2-4]. (See 'Primary hyperoxaluria type 2' below.)
Unlike the AGT of PH type 1, this enzyme, although predominantly expressed in the liver, has a wide tissue distribution . Pathologic variants of GRHPR result in increased amounts of glyoxylate and hydroxypyruvate, which are converted by lactate dehydrogenase to oxalate and L-glycerate (figure 1). These metabolites are excreted in excessive amounts in the urine, which in the case of oxalate, leads to recurrent kidney stones.
The GRHPR gene maps to chromosome 9p11 and encodes for a 36 kDa protein . More than 40 mutations have been described and include deletions, insertions, missense, and nonsense mutations [4,15]. The most common mutation occurring in approximately 40 percent of cases is a deletion of a single base pair in exon 2 (c.103delG).
●PH type 3 (MIM #613616) is due to variants of HOGA1 that encode the liver-specific mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme. This enzyme, expressed in the liver and the kidney, is the final step of the hydroxyproline degradation pathway within the mitochondria and catalyzes the cleavage of 4-hydroxy-2-oxoglutarate (HOG) to pyruvate and glyoxylate (figure 1) [16,17]. PH3 is the mildest form of PH and appears to account for approximately 5 to 10 percent of genetically characterized cases [2-4,18,19]. However, the prevalence of PH type 3 may be greater than previously published clinical studies reported. (See 'Primary hyperoxaluria type 3' below and 'Epidemiology' below.)
●Other – Two additional groups of PH patients have also been identified:
•Eleven percent of families in a study of 355 patients (301 families) registered in the Rare Kidney Stone Consortium PH registry (RKSC PH registry) had a PH phenotype but no variant in any of the three genes associated with PH (AGXT, GrHPR, and HOGA1) . These patients presented between four and nine years of age, had lower urine oxalate excretion than PH types 1 and 2, and did not tend to progress to ESKD.
•Two unrelated patients with calcium oxalate stones and variants in the SAT1 sulfate-oxalate transporter, encoded by SLC26A1, have been reported .
Genotype/phenotype correlation — PH type 1 is the most severe form of PH as patients are more likely to progress to ESKD and do so at an early age [3,4,21,22]. However, patients with PH type 2 may also develop ESKD. Patients with type 3 disease present at an earlier age than those with types 1 and 2 but typically have a lower urinary oxalate production rate and slower decline in kidney function. It remains uncertain whether type 3 disease progresses to ESKD. (See 'Primary hyperoxaluria type 3' below.)
For all three PH types, there is variable expression, even among family members with the same genotype . This was illustrated in one study that reported differences of greater than 20 years in the onset of ESKD between siblings with PH type 1 . In addition, within families with PH types 2, disease expression varies with one affected sibling progressing to ESKD, whereas the other siblings only had occasional symptomatic kidney stones.
There appears to be a closer correlation between genotype and phenotype for specific mutations of the AGXT gene. In particular, the most common variant AGXT p.Gly170Arg (reported allelic frequency of 21.5 percent in White patients) is due to a mistargeting allele and results in a milder PH1 phenotype . Pyridoxine treatment significantly reduces urinary oxalate excretion in patients with this variant, resulting in better long-term outcomes when the diagnosis is made early enough for medical intervention [21,23,24]. A similar positive response to pyridoxine therapy is also seen in patients with AGXT p.Phe152Ile mutations . (See 'Medical management' below.)
Effects of oxalate deposition — The excess oxalate that is produced in PH is primarily excreted by the kidneys. As kidney function declines, plasma oxalate levels increase, and calcium oxalate is deposited into other tissues, resulting in systemic oxalosis and manifestations outside the kidney.
●Kidney injury – The increased urinary excretion of oxalate results in urinary calcium oxalate supersaturation, which leads to crystal aggregation, kidney stones, and/or nephrocalcinosis (picture 1 and image 1).
PH type 1 is the most severe form of PH. Patients with PH type 1 have higher urine oxalate levels and higher incidence of nephrocalcinosis than the other two types of PH. In patients with PH type 1, urinary oxalate excretion exceeds 1 mmol/1.73 m2 per day (normal <0.5 mmol/1.73 m2 per day) . The presence of nephrocalcinosis is associated with increased risk for kidney failure, while the number of stones and stone events are not significantly associated with a risk of kidney failure . It is thought that nephrocalcinosis can cause kidney parenchymal inflammation and fibrosis and, if persistent, ESKD . Other urinary complications associated with kidney stones, such as infection and obstruction, also contribute to kidney damage.
●Systemic oxalosis – As the glomerular filtration rate (GFR) falls below 30 to 40 mL/min per 1.73 m2, plasma oxalate levels increase because of reduced urinary oxalate excretion . When plasma oxalate exceeds 30 micromol/L, which is the plasma supersaturation threshold for calcium oxalate, calcium oxalate is deposited into other tissues including the retina, myocardium, vessel walls, skin, bone, and the central nervous system, which leads to oxalosis with the non-kidney manifestations of PH. (See 'Systemic oxalosis' below.)
EPIDEMIOLOGY — Primary hyperoxaluria (PH) is a rare disorder. PH type 1, which accounts for approximately 80 percent of cases, has an estimated prevalence of between one to three per million in Europe and North America [27-29]. However, this estimation does not account for potential underreporting, especially for the less severe types 2 and 3, and may change with the increasing availability of molecular testing .
Carrier frequency, based on the known pathologic alleles, was estimated at 1 in 58,000 in a study of genetic testing in 355 patients from the Rare Kidney Stone Consortium PH registry population, using data from the National Heart, Lung, and Blood Institute Exome Sequencing Project . In this study, the prevalence of PH3 (the least severe type) was predicted to be the same as PH1 and twice as common as PH2. Population carrier rate was calculated to be lower in Black Americans than White Americans (ie, European ancestry).
In North America, PH type 1 is responsible for approximately 0.1 percent of cases of chronic kidney disease in children and is the primary diagnosis in 0.5 percent of children who undergo kidney transplantation .
CLINICAL AND LABORATORY MANIFESTATIONS
Primary hyperoxaluria type 1 — Primary hyperoxaluria (PH) type 1 is the most severe form of PH as these patients are more likely to progress to end-stage kidney disease (ESKD) and do so at an earlier age [3,4,21,22].
Age of presentation — The age at presentation is variable because of marked heterogeneity of disease expression. The median age at diagnosis is approximately 5 to 5.5 years of age but ranges from less than one year of age to over 50 years of age [4,31,32].
Kidney manifestations — Five clinical presentations of PH type 1 have been described based on the age of presentation and kidney manifestations [21,33,34]:
●Infant with oxalosis (26 percent) – Infants generally present before six months of age with nephrocalcinosis and kidney impairment [21,35,36]. In a case series of 78 infants, presenting symptoms and findings included nephrocalcinosis (91 percent), failure to thrive (22 percent), urinary tract infection (21 percent), and ESKD (14 percent) . ESKD developed at a mean age of three years and, in many cases, was present at the time of diagnosis.
●Child with recurrent kidney stones and rapid decline in kidney function (30 percent) – In these patients, the first symptoms are those usually associated with kidney stones (renal colic, hematuria, and urinary tract infection) and, occasionally, bilateral obstruction with acute kidney failure [2,21,37]. The calcium oxalate stones formed in patients with PH are bilateral and radiopaque on radiologic examination and are often seen in association of diffuse nephrocalcinosis.
●Adult with occasional stone formation (30 percent).
●Recurrent disease after kidney transplantation (10 percent).
●Family screening (approximately 10 to 15 percent) – Compared with patients diagnosed because of clinical suspicion, those identified after family screening were younger and had fewer number of stones at the time of diagnosis [3,21]. However, decline in kidney function and risk of developing ESKD were similar in both groups .
Early diagnosis is critical so that intensive medical therapy can be initiated that will delay the progression of ESKD. However, late detection is common and results in a significant number of patients who have ESKD at the time of diagnosis [2,38]. (See 'Medical management' below.)
ESKD develops in approximately one-half of patients by young adulthood without early diagnosis and medical intervention [3,21,22,36]. The rapidity of ESKD progression is variable and is dependent on residual enzyme activity and the response to pyridoxine .
Systemic oxalosis — When the glomerular filtration rate (GFR) falls below 30 to 40 mL/min per 1.73 m2, the combination of oxalate overproduction and reduced urinary oxalate excretion results in systemic oxalosis with potential calcium oxalate deposition in the heart, blood vessels, joints, bones, and retinas [14,40-42]. (See 'Effects of oxalate deposition' above.)
Deposition in these organs can lead to the following clinical manifestations:
●Cardiac – Cardiac conduction defects that may result in cardiac arrest .
●Circulation – Poor peripheral circulation that results in distal gangrene and difficulties with vascular access for hemodialysis.
●Bone and joints – Bone manifestations that include pain, erythropoietin-resistant anemia, and an increased risk of spontaneous fracture [34,44]. Oxalate deposition may be seen as dense suprametaphyseal bands on x-rays and are most prominent in the metaphyses of long bones and trabecular bones. Osteoarticular manifestations are severe in patients who have been on dialysis for more than one year.
Oxalate deposition in the joints can lead to synovitis with reduced mobility and pain.
●Vision – Oxalate deposition in the retinal epithelium and the macula can cause diminished visual acuity .
●Bone marrow – Oxalate deposition in the bone marrow leading to pancytopenia .
●Other findings include hypothyroidism , peripheral neuropathy, dental problems (tooth pain, root resorption, and pulp exposure), and skin manifestations including livedo reticularis, peripheral gangrene, and metastatic calcinosis cutis [48,49]. (See "Calcinosis cutis: Etiology and patient evaluation", section on 'Metastatic calcinosis cutis'.)
Primary hyperoxaluria type 2 — PH type 2 is generally a milder disease than PH type 1 as the risk for ESKD is lower and kidney function deterioration is slower [2,4,50-52].
Information on clinical findings is limited due to the rarity of the disease and is based on data from observational case series. The following clinical manifestations are based on findings from two large case series [4,50].
●Age at presentation and diagnosis – The reported median ages of first-noted symptom vary from 3.2 to 7.4 years. However, the age of presentation ranges from 0.1 to 41 years of age.
•Kidney stones – The most common presentation is due to symptoms related to kidney stones, which include gross hematuria, renal colic, urinary tract infection, and, infrequently, urinary obstruction [50,51]. Kidney stones and nephrocalcinosis occur in more than 80 percent of patients.
•Kidney function impairment and ESKD – Approximately one-quarter to one-third of patients with PH type 2 will progress to ESKD. The median age for reaching ESKD was 40 years (range 34 to 48 years of age), which is older than what is typical for PH type 1 disease.
Approximately one-third of patients maintained normal kidney function and the remainder had evidence of kidney dysfunction.
●Systemic oxalosis – Patients who progress to ESKD were also at risk for systemic oxalosis (eg, retinal deposits, cardiomyopathy, and conduction abnormalities).
Primary hyperoxaluria type 3 — Data on the clinical manifestations and course of PH type 3 are more limited because the genetic basis for the disorder was first described in 2010. Patients with PH type 3 typically present early in life (mean age two years) with symptoms due to recurrent kidney stones (eg, hematuria, pain, and/or urinary tract infection) . Although it was thought that after six years of age, recurrence of kidney stones was unlikely, data from the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry indicated that the risk of recurrent stone disease was similar for patients with type 3 disease compared with those with types 1 and 2, and the risk continues through adulthood . However, patients with type 3 disease have milder kidney disease than either type 1 or 2 and typically do not progress to ESKD [4,19,53-55]. In one study that included 38 patients with type 3 disease, one patient did progress to ESKD but kidney injury may have been aggravated by recurrent surgical procedures to remove kidney stones . Patients may develop mild kidney function impairment [53,56].
Step-wise diagnostic assessment — The diagnosis of primary hyperoxaluria (PH) is made in a stepwise fashion based on:
●Clinical suspicion due to the presence of clinical manifestations.
●Metabolic testing demonstrating elevated urinary oxalate excretion.
●If no variant has been found, the diagnosis of PH type 1 and 2 can be made by a liver biopsy demonstrating absent or significantly reduced AGT or GRHPR activity .
Clinical suspicion — Because of the rarity of PH, a strong clinical suspicion is needed to ensure there is not a delay in diagnosis, as the efficacy of treatment is dependent on early diagnosis. The diagnosis of PH should be suspected in children and infants with any of the following findings [31,40,61,62]:
●Pure calcium oxalate monohydrate kidney stones (also referred to as whewellite) (picture 2).
●Nephrocalcinosis, especially if associated with a decrease in glomerular filtration rate (GFR).
Referral — All patients with a confirmed diagnosis of PH should be under the care of a nephrologist. Patients should be referred to a nephrologist as soon as a diagnosis of PH is suspected. As a first step toward diagnosis, a primary care clinician can obtain urinary oxalate levels if the test is available.
Increased urinary oxalate excretion — A clinical diagnosis relies on metabolic screening that demonstrates a markedly increased urinary excretion of oxalate (ie, greater than 1 mmol/1.73 m2 per day [90 mg/1.73 m2 per day]) . Patients with type 1 and 2 disease have higher urinary excretion of oxalate with levels as high as 1.5 to 3 mmol/1.73 m2 per day (135 to 270 mg/1.73 m2 per day). Normal urinary oxalate excretion is less than 0.5 mmol/1.73 m2 per day (45 mg/1.73 m2 per day) . Plasma oxalate concentration remains normal as long as the GFR is higher than 40 mL/min per 1.73 m2 .
In some patients, obtaining a 24-hour urine collection is difficult, especially in infants and small children who are not toilet trained. As a result, oxalate excretion can be evaluated by measuring the molar oxalate:creatinine ratio in spot urine samples. Although normative values for oxalate:creatinine (mmol/mmol) vary by age and the assay method [64-67], the generally acceptable normal values based on age used to screen for hyperoxaluria are [14,48,63]:
●Infants less than 6 months of age – <0.32 to 0.36
●Children between 6 months and 2 years of age – <0.13 to 0.17
●Children between 2 and 5 years of age – <0.098 to 0.1
●Children between 6 and 12 years of age – <0.O7 to 0.08
●Patients >16 years – <0.04
Plasma oxalate levels — Urinary oxalate measurements may be falsely low in patients with kidney insufficiency and progressive disease, which is common in patients with type 1 disease. In this setting, plasma oxalate levels may be useful, as there is an inverse relation between plasma oxalate and kidney function in children with early stages of chronic kidney disease . For these patients with reduced kidney function, increased plasma oxalate and glycolate concentrations can be used to help support the diagnosis of PH [68-70]. However, others have reported that plasma oxalate may not be a valid endpoint for clinical studies in PH 1 patients with normal or stable kidney function .
Differentiating between the primary hyperoxaluria types — Since all three types of PH have elevated urinary oxalate excretion, they can be distinguished from one another by assessing urinary excretion of metabolites associated with a specific underlying genetic cause of PH.
●Glycolate and PH type 1 – In general, hyperoxaluria plus increased urinary excretion of glycolate is strongly suggestive, but not absolutely diagnostic, of PH type 1 (normal urinary glycolate excretion is 0.5 mmol/1.73 m2 per day [45 mg/1.73 m2 per day]) .
For spot urine samples, the following are values of the molar glycolate:creatinine ratio based on age :
•Infants less than 6 months of age – <0.36 to 0.42
•Children between 6 months and 2 years of age – <0.24 to 0.29
•Children between 2 and 5 years of age – <0.19 to 0.22
•Children between 6 and 12 years of age – <0.16 to 0.18
•Patients >16 years – >0.09 to 0.12
●L-glyceric acid and PH type 2 – Patients with type 2 PH typically have elevated levels of L-glyceric acid (>28 mmol/mol creatinine), which is not observed in patients with type 1 or type 3 disease [4,72]. (See 'Primary hyperoxaluria type 2' above.)
●Hydroxy-oxo-glutarate and PH type 3 – Increased urinary excretion of hydroxy-oxo-glutarate can be used to diagnose PH type 3 [53,58,59].
Genetic testing — Definitive diagnosis is possible by molecular testing for variants in any of the three known causative genes for PH (AGXT, GRHPR, and HOGA1). Genetic testing options include the following :
●Whole-gene sequencing should be performed if there is a high clinical index of suspicion.
●Next-generation sequencing has comparable diagnostic performance with manual or automated first-generation sequencing for the diagnosis of PH and screens for all forms of PH simultaneously, ensuring prompt diagnosis and decreased cost . (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Terminology and evolution of technologies'.)
●Targeted mutation analysis screens for the most common variants:
•For PH type 1 – The detection rate is dependent on the number of AGXT variants used in the screening panel but generally ranges from 50 to 70 percent. In one study, the most common mutation (p.Gly170Arg) was found in 37 percent of alleles followed by a frame shift mutation (c.33_34insC) in 11 percent .
A list of available laboratories for genetic testing can be found on the National Institutes of Health Genetic testing registry website.
Prenatal diagnosis — Deoxyribonucleic acid (DNA) obtained from chorionic villi or amniotic cells is analyzed for the identified mutations found in the family, allowing detection of affected fetuses.
Liver biopsy — Prior to the availability of genetic testing, the diagnosis of PH type 1 and 2 were confirmed by liver biopsy that demonstrated AGT deficiency for patients with PH type 1 disease and decreased GRHPR activity for those with type 2 disease. Evaluation of the hepatic tissue includes quantification of enzymatic activity, an immunoblot to analyze the protein, and an immunoelectronic examination of these enzymes .
If genetic testing is not available or a gene mutation has not been identified in a patient in whom there is a strong clinical suspicion for PH, liver biopsy to confirm the diagnosis is required prior to liver transplantation.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of primary hyperoxaluria (PH) includes:
●Dietary hyperoxaluria – Ongoing excessive oxalate intake due to consumption with foods rich in oxalate such as chocolate, cocoa, leafy green vegetables (eg, rhubarb and spinach), black teas, nuts, peanut butter, and starfish fruit .
●Enteric hyperoxaluria – Increased intestinal oxalate absorption associated with fat malabsorption due to malabsorptive bariatric surgery, small bowel disease, or cystic fibrosis . (See "Kidney stones in children: Epidemiology and risk factors", section on 'Hyperoxaluria and oxalosis' and "Chronic complications of short bowel syndrome in children", section on 'Hyperoxaluria and kidney stones'.)
●Combinations of etiologies – Absence of intestinal oxalate degrading bacteria (Oxalobacter formigenes) and relatively high oxalate diets or small bowel disease and cystic fibrosis.
Metabolic screening differentiates the disorders above from PH. Although elevated urinary oxalate excretion can be seen in patients with excess intake of oxalate (dietary hyperoxaluria), or in patients with increased intestinal oxalate absorption due to small bowel diseases (enteric hyperoxaluria), these levels are usually typically below 1 mmol/day (90 mg/day), which are below the levels seen in patients with PH . In addition, genetic confirmation of PH excludes these disorders. (See 'Increased urinary oxalate excretion' above.)
EVALUATION AFTER DIAGNOSIS — Once the diagnosis of primary hyperoxaluria (PH) has been confirmed, additional evaluation assesses the function of potentially affected organs [48,62].
●Kidney function is evaluated by obtaining serum creatinine levels as a measure of glomerular filtration rate (GFR). (See "Chronic kidney disease in children: Clinical manifestations and evaluation", section on 'Serum creatinine and GFR'.)
●Bone radiographs to detect radiodense metaphyseal bands and diffuse demineralization.
●Thyroid function tests to detect thyroid dysfunction. (See "Laboratory assessment of thyroid function".)
●Electrocardiogram to detect abnormalities in cardiac conduction.
●Hemoglobin measurement to detect anemia due to chronic kidney disease or as a result of oxalate deposition in bone marrow.
●In patients with systemic oxalosis, further evaluation to determine the extent of end-organ involvement should include eye evaluation (including slit lamp examination), bone density determination, electrocardiography, and echocardiography.
Overview — Information on the management of primary hyperoxaluria (PH) is primarily derived from treating patients with PH type 1, the most common form of the disease. The efficacy of treatment in PH type 1 is dependent on early diagnosis. In particular, for patients with PH type 1, the initiation of medical management (reduction of urinary calcium oxalate excretion) as soon as possible prolongs kidney function, which delays end-stage kidney disease (ESKD) and potentially minimizes non-kidney sequelae. (See 'Medical management' below.)
Through 2021, our clinical practice for individuals with ESKD due to PH has been combined liver and kidney transplantation. Liver transplantation provides the definitive cure for PH type 1 by restoring the missing enzyme, which lowers oxalate production to the normal range. However, with the introduction of new ribonucleic acid interference (RNAi) drugs, it is unclear whether liver transplantation will be necessary in the future. The hope is that these new interventions will significantly alter oxalate production, thereby slowing the progression of kidney injury and the risk of ESKD [7,78,79]. (See 'Transplantation' below.)
Medical management — Medical management is focused on reduction of urinary calcium oxalate saturation and oxalate production, thereby minimizing kidney oxalate deposition and delaying the progression of kidney injury [62,80]. (See 'Effects of oxalate deposition' above.)
General measures in all patients — Management for all forms of PH includes the following modalities, all of which may be started simultaneously [40,61,62,81,82]:
●Increased fluid intake – Large fluid intake resulting in a high urinary output (greater than 3 L/day per 1.73 m2) is the most effective therapy to decrease tubular fluid oxalate concentration and diminish intratubular oxalate deposition. A gastric tube or a percutaneous gastrostomy may be necessary in young children to maintain this high urine flow around the clock.
●Inhibition of calcium oxalate precipitation – Alkalinization of urine with potassium citrate can reduce urinary calcium oxalate saturation by forming complexes with calcium, which decreases stone formation. We use oral potassium citrate at a dose of 0.15 g/kg divided into two or three doses per day. If kidney function is impaired and plasma potassium is increased, sodium citrate can replace potassium citrate.
Other inhibitors of calcium oxalate crystallization, which are used selectively, include neutral phosphate (20 to 30 mg/kg) or magnesium oxide (500 mg/day per m2), also given orally, divided into two or three doses per day. Phosphate supplements should be discontinued in patients with impaired kidney function who develop hyperphosphatemia. If a patient's glomerular filtration rate (GFR) decreases, a serum phosphate level should be obtained. If hyperphosphatemia is present, phosphate supplementation should be stopped in order to prevent phosphate accumulation and exacerbation of secondary hyperparathyroidism. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)" and "Kidney stones in children: Prevention of recurrent stones", section on 'Hyperoxaluria and oxalosis'.)
●Dietary oxalate restriction – Although intestinal oxalate absorption is lower in patients with PH compared with healthy subjects, foods with high oxalate content (such as tea, chocolate, spinach, and rhubarb) should be restricted from their diet . However, as most of the oxalate is of an endogenous source, these dietary measures are of minor impact in most patients.
Additional therapies for primary hyperoxaluria type 1 — In addition to the general measures above that are applicable to all types of PH, pyridoxal phosphate and lumasiran are additional therapies for PH type 1 specifically. Both medications may be started simultaneously.
●Pyridoxine supplementation – For all patients with type 1 PH, we suggest a three to six month trial of high-dose pyridoxine (pyridoxal phosphate) based upon case series reporting that the combination of pyridoxine and a neutral phosphate started at an early age slows the progression to ESKD [81,84]. We begin pyridoxine therapy at a dose of 5 mg/kg divided into one or two doses per day. We then assess the response to therapy by comparing the 24-hour urine oxalate excretion before and after treatment. A positive response is defined as a reduction in urinary oxalate of greater than 30 percent. In patients who are responsive, we continue pyridoxine indefinitely or until liver transplantation is performed. If the patient has not had a positive response to pyridoxine after four to six weeks, the dose can be titrated up to a maximum of 20 mg/kg per day. The medication is discontinued if there is no significant decrease in urinary oxalate excretion. Large doses of pyridoxine may induce sensory neuropathy .
Pyridoxine is a coenzyme of alanine-glyoxylate aminotransferase (AGT) that promotes the conversion of glyoxylate to glycine, rather than to oxalate. Approximately 10 to 30 percent of patients with PH type 1 will respond to pyridoxine therapy with a significant reduction of urinary oxalate excretion, particularly those patients with homozygous AGXT p.Gly170Arg or p.Phe152Ile mutations [14,23,81,86-90].
●Lumasiran – Lumasiran is an RNAi therapeutic agent that targets glycolate oxidase resulting in depletion of the substrate for oxalate synthesis, thereby reducing oxalate production [91-93]. Our practice is to start lumasiran as a first-line treatment in patients with confirmed PH type I. Lumasiran is administered subcutaneously and dosing is weight-based:
•For patients <10 kg, the initial dose is 6 mg/kg monthly for three months, followed by 3 mg/kg monthly
•For patients 10 to 20 kg, the initial dose is 6 mg/kg monthly for three months, followed by 6 mg/kg every three months
•For patients >20 kg, the initial dose is 3 mg/kg monthly for three months, followed by 3 mg/kg every three months
The US Food and Drug Administration approved lumasiran as initial therapy for PH type 1 in 2020 [94,95]. The approval was based on two clinical studies in patients, including children <6 years of age, which reported that subjects experienced a >50 percent decrease in urinary oxalate excretion and no significant adverse effects, with subsequent confirmatory studies [78,96,97]. In a series of 18 infants and children <6 years with PH type 1, lumasiran reduced spot oxalate:creatinine ratio by 72 percent at 6 and 12 months . In patients with PH type 1 with advanced kidney disease, lumasiran results in substantial reductions in plasma oxalate, with an acceptable safety profile . Long-term follow-up is needed to assess the efficacy of lumasiran in reducing the risk of ESKD, reducing stone formation, and stabilizing kidney function. The annual cost of this medication is estimated at USD $379,100 , which will impact its clinical accessibility.
Investigational agents — The following agents are in development and are not routinely used in clinical practice.
●Nedosiran – Data from two phase I clinical trials for nedosiran, a second-generation RNAi therapeutic agent that targets the messenger RNA (mRNA) encoding hepatic lactate dehydrogenase A, suggest that nedosiran may be a safe and effective therapeutic option for the treatment of all types of PH [100-102]. A case report of a single index patient treated with nedosiran also described a favorable response to the treatment .
●O. formigenes – Enhancing oxalate elimination by the gastrointestinal tract is another potential method to reduce tissue and body oxalate levels. One proposed mechanism is the administration of O. formigenes, an obligate anaerobic colonic bacterium that promotes endogenous oxalate intestinal excretion [104,105]. We do not routinely administer O. formigenes therapy, as evidence regarding its use in patients with PH is inconclusive. Results from clinical trials are inconsistent on whether urinary oxalate is reduced in patients who received oral O. formigenes therapy compared with those given placebo [106-109]; similar numbers of serious adverse effects were reported. Further study is needed to determine whether O. formigenes therapy effectively and safely prevents or slows the progression of ESKD in patients with PH.
●O. formigenes-derived bioactive factors – Although the administration of O. formigenes has not been shown to improve outcome, data from in vitro human cell cultures and a mouse model using O. formigenes culture-conditioned medium have suggested a potential role for O. formigenes-derived bioactive factors as a novel therapeutic agent for prevention and/or treatment of hyperoxaluria .
●Stiripentol – Stiripentol is an antiseizure medication that decreases hepatic oxalate production, is a potentially promising agent. Stiripentol reduced urinary oxalate excretion and kidney oxalate deposition in rat model studies and decreased urinary oxalate excretion in a 17-year-old patient with severe type 1 hyperoxaluria . However, another case report suggested that stiripentol was not clinically effective in two patients with PH type 1 . A phase 2 clinical trial (NCT03819647) is planned to study the effects of this drug in reducing urinary oxalate excretion in patients with hyperoxaluria .
Monitoring response to therapy — Response to therapy in a stable patient should be assessed with a 24-hour urinary oxalate excretion test and urinary calcium level every three months. Urinary oxalate concentration should remain below 0.4 mmol/l and urinary calcium concentration below 4 mmol/l. If a patient is unstable, these tests may be performed more often. Other tests performed (eg, serum creatinine, kidney ultrasound) depend on the response to therapy demonstrated by the urinary oxalate excretion.
Management of kidney stones — Intervention is required when stones obstruct the urinary tract. Nephrostomy, ureteroscopy, and ureteral JJ stent are preferred interventions for stone removal. Open surgical removal may precipitate acute kidney failure and extracorporeal shock-wave lithotripsy may harm the kidney because of the potential presence of nephrocalcinosis and microlithiasis within the kidney [115-117]. However, repeated surgical interventions may also contribute to kidney injury and ESKD . (See "Kidney stones in children: Acute management", section on 'Urologic intervention'.)
Dialysis — Intensive dialysis (eg, five-hour daily hemodialysis [HD] sessions, nocturnal HD, or a combination of HD and peritoneal dialysis [PD]) is needed to try to match daily oxalate production, but, in many PH patients, even intensive dialysis therapy remains inadequate to keep up with their daily oxalate production . The maximal oxalate elimination via conventional HD and PD is 950 to 1440 micromol/day, which is significantly lower than the daily oxalate production of 3500 to 7500 micromol in patients with PH type 1 [120,121]. Predialysis plasma oxalate ranges between 100 and 200 micromol/L with a 60 to 80 percent reduction after hemodialysis. However, plasma oxalate returns to 80 percent of the predialysis value within 24 hours and 95 percent 48 hours after dialysis . As a consequence, despite standard maintenance dialysis therapy, plasma oxalate typically exceeds the supersaturation threshold of 30 micromol/L during a substantial amount of time between dialysis treatments, thereby increasing the risk and progression of systemic oxalosis. (See 'Systemic oxalosis' above and 'Effects of oxalate deposition' above.)
Intensive dialysis therapy may be useful prior to kidney transplantation to decrease plasma oxalate as much as possible to reduce subsequent oxalate deposition and injury in the kidney allograft. (See 'Isolated kidney transplantation' below.)
Choice of transplant option — The optimal transplantation strategy for patients with PH of all types remains uncertain . Regardless of the chosen procedure, the surgery should be performed at a center with expertise in transplantation and the care of patients with PH. There are four possible transplantation options:
●Combined liver and kidney transplantation
●Sequential liver and kidney transplantation
●Isolated liver transplantation
●Isolated kidney transplantation
Liver transplantation is the only curative intervention for PH type 1 because it corrects the underlying enzymatic defect due to mutations of the AGXT gene. Preemptive liver transplant in patients with GFRs greater than 40 mL/kg per 1.73 m2 has been proposed as curative treatment. However, this presupposes progression of kidney disease despite aggressive medical management and exposes the patient to the known risk factors associated with liver transplantation and removal of a native liver that is normal except for the absence or reduction in AGT activity. Complications include those due to immunosuppressive therapy (eg, infections or adverse drug effects, such as calcineurin inhibitor-induced nephrotoxicity), secondary malignancy, and failure of the liver allograft. If preemptive liver transplantation is considered, the optimal timing is unknown, as there are no data that provide an accurate prediction of the clinical course in patients who are diagnosed prior to significant kidney damage and treated with aggressive medical management, especially patients who are responsive to pyridoxine therapy.
For patients with PH type 1 with significant chronic kidney disease, combined liver and kidney transplantation has been advocated over isolated kidney transplantation. This is because replacement of the native liver corrects the underlying metabolic defect and thus reduces the exposure of the kidney graft to the damaging effects of hyperoxaluria. However, even with combined liver and kidney transplantation, the new allograft is still exposed to some hyperoxaluria because tissue stores of oxalate are mobilized with the return of kidney function. After the transplant, urine oxalate can remain elevated for many months due to the slow resolubilization of systemic calcium oxalate. As long as urinary oxalate remains elevated, these patients should continue with a high fluid intake and treatment with crystallization inhibitors to protect the transplanted kidney from calcium oxalate damage. Long-term data comparing these approaches are insufficient to determine the optimal approach. As an example, death-censored kidney allograft survival is greater in recipients of combined liver and kidney transplants compared with recipients of isolated kidney transplants, but patient survival may be similar or even lower [123-125]. The duration of kidney allograft survival is also unknown in patients with isolated kidney transplantation who are treated with intensive medical therapy immediately after transplantation, especially in those who are responsive to pyridoxine therapy.
For patients with PH type 2 who progress to ESKD, data are insufficient to guide the optimal choice of transplantation. Although isolated kidney transplantation has been the recommended approach [14,123,126], immediate recurrence and subsequent graft loss were reported in a pediatric patient with PH type 2 who underwent isolated kidney transplantation . Case reports of combined liver/kidney transplant in adults have shown normalization of plasma oxalate, urine oxalate, and urine glycerate levels, including in one adult patient who experienced a rapid and severe relapse of oxalate nephropathy after isolated kidney transplant [128,129]. Further information is required to determine whether liver transplantation is beneficial in patients with PH type 2 disease .
Combined liver and kidney transplantation — Combined liver and kidney transplantation has become the treatment used in children with PH type 1 with progressive kidney disease [35,123,130-133]. The liver provides the missing enzyme, thereby lowering oxalate production to the normal range. This modality should be considered only after confirming that the diagnosis is PH type 1. The outcome of simultaneous transplantation is probably best when the procedure is performed when the GFR falls below 40 mL/min per 1.73 m2 and prior to marked tissue oxalate deposition.
The following observational outcome data demonstrate that combined liver and kidney transplantation had a better graft survival compared with isolated kidney transplantation.
●The International Primary Hyperoxaluria Registry compared outcomes of different transplantation approaches for patients who were transplanted between 1976 and 2009 . In this cohort, 32 patients received an isolated kidney graft, and 26 patients received a combined liver and kidney. Three patients with a combined liver and kidney transplantation died with functioning allografts, which resulted in a lower five-year patient survival (67 versus 100 percent). However, the three-year kidney graft survival for survivors was higher with combined grafts compared with isolated kidney graft (95 versus 56 percent). Of note, patients with isolated kidney transplants had a greater delay in diagnosis (including 11 patients who were undiagnosed at the time of transplantation) and were more likely to have their transplantation performed before 2000.
●In a European report of patients less than 19 years old, kidney survival at three months and five years was only 54 percent and 14 percent for isolated kidney transplantation, compared with 82 percent and 76 percent for combined liver and kidney transplantation, suggesting that isolated kidney transplantation is not a good option in children who have progressed to kidney failure .
●Long-term outcome of a consecutive French case series of 54 patients with transplants performed between 1979 and 2010 reported similar 10-year patient survival between liver and kidney transplantation (n = 33) and isolated kidney transplantation (n = 21) groups (78 versus 70 percent) . Ten-year kidney graft survival was better after combined liver and kidney transplantation (87 versus 13 percent).
After combined transplantation, there is gradual mobilization of tissue oxalate deposits, and elevated urinary oxalate excretion may persist for as long as or even longer than two years as tissue stores are removed . The same management strategies used for patients with isolated kidney transplant are employed in patients undergoing combined liver and kidney transplantation to decrease hyperoxaluria. This includes aggressive medical management (high fluid intake, and the administration of neutral phosphate, potassium citrate-citric acid, and/or magnesium oxide), and the administration of pyridoxine in responsive patients. The duration of medical intervention varies, depending on the amount of oxalate tissue stores. Medical management is discontinued when urine oxalate excretion returns to normal values. Bilateral native nephrectomy at the time of transplantation reduces oxalate stores . (See 'Medical management' above and 'Isolated kidney transplantation' below.)
Sequential liver and kidney transplantation — Another option is sequential transplantation (first liver followed by kidney transplantation), which has been performed in children with PH type 1 and ESKD [135-137]. The rationale underlying this approach is the initial liver transplant allows intensive dialysis to clear the stores of tissue oxalates in patients who have been on dialysis for prolonged periods of time, thereby reducing the risk of kidney injury after kidney transplantation. In addition, sequential transplantation may be performed in small recipients in whom a combined simultaneous transplantation is not feasible, because of anatomical reasons or medical instability [131,137,138].
The medical management of patients after sequential transplantation is the same as that used for patients who undergo combined liver and kidney transplantation discussed above.
Isolated liver transplantation — Isolated liver transplantation has been proposed for patients with progressive disease who still have a GFR between 40 to 60 mL/min per 1.73 m2 . In a case series of 18 individuals with a GFR >50 mL/kg/1.73 m2, the seven individuals who underwent preemptive liver transplantation experienced preserved kidney function; median eGFR was 72 (range 50 to 89) mL/kg/1.73 m2 at transplantation and 104 mL/kg/1.73 m2 (range 86 to 108) at follow-up 6 to 27 years later . By contrast, in a comparison group of 11 patients who were managed conservatively, eight reached stage 5 CKD and two died. Similar outcomes were seen in earlier case reports [136,140-144].
Liver transplantation requires native hepatectomy, even though the liver is normal in all other aspects, because any remaining defective hepatic cells will continue to produce large amounts of oxalate. The significant morbidity and mortality associated with liver transplantation has led to hesitation to adopt preemptive liver transplantation in the absence of significant kidney impairment [124,145,146]. Moreover, outcomes of conservative management have generally improved due to early diagnosis and initiation of intensive medical therapy, including lumasiran . (See "Liver transplantation in adults: Long-term management of transplant recipients".)
Isolated kidney transplantation — Isolated kidney transplantation has generally been supplanted by combined liver and kidney transplantation  because the experience of kidney transplantation alone in PH had been relatively disappointing, as oxalate deposition from newly formed and mobilized tissue oxalate led to loss of the allograft in many patients.
Data from the European Dialysis and Transplant Association on 98 PH patients with first transplant prior to 1990 showed a three-year graft survival rate of only 23 percent for living related donor kidneys and 17 percent for cadaver kidneys . In a study from the European Pediatric Nephrology Registry of 100 children who were less than 19 years and received an isolated kidney transplantation between 1979 and 2009, graft survival in those with PH was lower compared with that of children without PH at one year (46 versus 95 percent), three years (28 versus 90 percent), and five years (14 percent versus 85 percent) follow-up . Similar dismal results were observed in a report of a single center's transplantation experience .
Isolated kidney transplantation may be an option in selected patients who are responsive to pyridoxine, such as those with homozygous AGXT p.Gly170Arg or p.Phe152Ile mutations [62,149,150]. However, these patients should not progress to kidney failure if the diagnosis is made early and timely aggressive medical management including pyridoxine therapy is provided prior to extensive kidney injury. Isolated kidney transplantation may also be an option in adults with a late-onset form of the disease .
PROGNOSIS — Prognosis is different for the different types of primary hyperoxaluria (PH).
●Patients with type 1 PH have had the most dire prognosis, with end-stage kidney disease (ESKD) developing in approximately one-half of these patients by young adulthood without early diagnosis and treatment [3,21,22,36]. How quickly a patient with PH 1 progresses to ESKD is variable and is dependent on residual enzyme activity and response to treatment. RNA interference (RNAi) agents, such as lumasiran, appear to slow the progression of chronic kidney disease, including ESKD, which may have an impact on prognosis for patients with PH type 1.
●PH type 2 is generally a milder disease than PH type 1 as the risk for ESKD is lower and kidney function deterioration is slower [2,4,50-52]. Approximately one-quarter to one-third of patients with PH type 2 will progress to ESKD. Approximately one-third of patients with PH 2 maintain normal kidney function.
●Patients with type 3 disease have milder kidney disease than either type 1 or 2. These patients typically develop mild kidney function impairment but do not progress to ESKD [4,19,53-55].
ADDITIONAL INFORMATION — Additional information about primary hyperoxaluria can be obtained from the following:
•The Oxalosis and Hyperoxaluria Foundation
201 East 19th Street, Suite 12E
New York, NY 10003
Email – [email protected]
•University College London Hospitals clinical biochemistry service provides metabolic and genetic testing
•National Institutes of Health Genetic testing registry lists laboratories that are available for genetic testing
SUMMARY AND RECOMMENDATIONS
●Definition and pathogenesis – Primary hyperoxaluria (PH) is a rare inborn error of glyoxylate metabolism characterized by the overproduction of oxalate, which is deposited as calcium oxalate in various organs. Deposition in the kidney may lead to end-stage kidney disease (ESKD) in some cases. (See 'Introduction' above and 'Effects of oxalate deposition' above.)
•PH type 1 (approximately 70 to 80 percent of cases based on clinical observational studies) is due to variants of the AGXT gene that encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). (See 'Primary hyperoxaluria type 1' above.)
•PH type 2 (10 percent of cases) is due to variants of glyoxylate reductase/hydroxypyruvate reductase that encodes the GRHPR gene.
•PH type 3 (5 percent of cases) is due to variants of HOGA1 gene that encodes the mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme, which catalyzes the cleavage of 4-hydroxy-2-oxoglutarate (HOG) to pyruvate and glyoxylate.
●Pathogenesis of end-organ damage – In patients with PH, increased urinary excretion of oxalate results in oversaturation of the urine with calcium oxalate, leading to kidney stones and nephrocalcinosis. Recurrent stones and progressive nephrocalcinosis cause kidney parenchymal inflammation and fibrosis, which, if persistent, may progress to ESKD. As kidney function deteriorates, plasma oxalate increases further, leading to calcium oxalate deposition into non-kidney tissues (systemic oxalosis), including the retina, myocardium, vessel walls, skin, bone, and central nervous system. (See 'Effects of oxalate deposition' above.)
•PH type 1 – The presentation of PH type 1 varies depending on age and clinical findings because of marked heterogeneity of disease expression. Affected infants and children generally present at a median age of five years (range from <1 year to over 50 years of age) with symptoms related to nephrocalcinosis, kidney stones, and/or chronic kidney disease. ESKD develops in approximately one-half of patients by young adulthood. As kidney function deteriorates, non-kidney manifestations due to systemic oxalosis develop and include cardiac conduction defects, bony pain and increased risk of fractures, and diminished visual acuity. (See 'Primary hyperoxaluria type 1' above.)
•PH type 2 – Patients with PH type 2 primarily present with recurrent kidney stones and may progress to ESKD, typically at an older age than patients with PH type 1 disease. Patients with progressive kidney dysfunction will also have evidence of systemic oxalosis. (See 'Primary hyperoxaluria type 2' above.)
•PH type 3 – Patients with PH type 3 generally present early in life (mean age two years) with kidney stones. In contrast with the other two forms of PH, patients with PH type 3 typically do not progress to ESKD. (See 'Primary hyperoxaluria type 3' above.)
●Diagnosis and referral – The diagnosis of PH is based on recognition of clinical findings suggestive of PH (eg, recurrent kidney stones or nephrocalcinosis), a markedly increased urinary oxalate excretion, and confirmation by molecular genetic testing. In cases where genetic testing is negative, liver biopsy demonstrating decreased or absent activity of AGT for type 1 disease and GRHPR for type 2 is used to confirm the diagnosis. Metabolic testing is useful in differentiation amongst the three different types. Patients should be referred to a nephrologist as soon as a diagnosis of PH is suspected. (See 'Diagnosis' above and 'Referral' above.)
●Differential diagnosis – The differential of PH includes secondary oxalosis due to increased oxalate intake or oxalate reabsorption due to small bowel disease. The different forms of PH are distinguished from these other conditions by higher urinary oxalate excretion rates and molecular testing. (See 'Differential diagnosis' above.)
●Management – Information on the management of PH is primarily derived from treating patients with PH type 1, the most common and severe form of the disease. The efficacy of treatment in PH type 1 is dependent on early diagnosis.
•Medical interventions – The following medical interventions reduce calcium oxalate deposition and kidney impairment in patients with PH types 1 and 2. (See 'Medical management' above.)
-For patients for all forms of PH, high fluid intake (greater than 3 L/day per 1.73 m2) is routinely provided to decrease tubular fluid oxalate concentration and diminish intratubular oxalate deposition with a goal of urinary oxalate concentration below 0.4 micromol/L throughout the entire 24-hour day.
-For patients with PH types 1 and 2, we suggest the use of agents that increase the solubility of calcium oxalate (Grade 2C). We use oral potassium citrate at a dose of 0.15 g/kg divided into two or three doses per day. Other agents include neutral phosphate (20 to 30 mg/kg) or magnesium oxide (500 mg/day per m2), also given orally and divided into two to three doses per day.
-For patients with PH type 1, we suggest a three-month trial of pyridoxine (Grade 2C). In approximately 30 percent of patients with PH type 1, pyridoxine reduces urinary oxalate secretion. Pyridoxine is not effective in patients with PH type 2.
-For patients with PH type 1, we recommend lumasiran as a first-line treatment (Grade 1B). Lumasiran is administered subcutaneously, and dosing is weight based. (See 'Additional therapies for primary hyperoxaluria type 1' above.)
●Transplantation – In patients with PH type 1 disease and ESKD, the main options are combined liver-kidney transplantation or sequential liver and kidney transplantation. Until more data are available to better inform the choice, we perform combined liver-kidney transplantation. For patients who are pyridoxine sensitive or have a late-onset form of the disease, isolated kidney transplantation is possible. (See 'Transplantation' above.)
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