Primary Hyperoxalurias

Inherited disorders of glyoxylate metabolism with endogenous oxalate overproduction — primary hyperoxaluria type 1 (AGXT), type 2 (GRHPR) and type 3 (HOGA1).

Literature and regulatory information updated: 6 November 2026.

0. Initial Reference Table

1. Introduction

The primary hyperoxalurias (PH) are three autosomal recessive inherited disorders of hepatic glyoxylate and hydroxyproline metabolism whose common consequence is excessive endogenous production of oxalate, an anion that the human body does not metabolise and that is eliminated almost exclusively by the kidney [8, 25]. High urinary oxalate concentration, combined with calcium, generates poorly soluble calcium oxalate crystals, which aggregate into stones (nephrolithiasis) or deposit in the renal parenchyma (nephrocalcinosis). When the glomerular filtration rate (GFR) falls to values close to 30 mL/min/1.73 m², daily production exceeds clearance, plasma oxalate rises and deposits in bone, heart, retina, vessels and other tissues, a picture termed systemic oxalosis [8, 16]. The French PNDS (French National Diagnosis and Care Protocol) defines primary hyperoxaluria as «maladie héréditaire du métabolisme aboutissant à une production excessive d'oxalate» and stresses that type 1 is the most severe and the most frequently diagnosed form [16].

The biochemical delineation of these disorders preceded the genetics by several decades. Frederick et al. demonstrated in vivo a defect of glyoxylate metabolism in 1963, and Hockaday et al. described the metabolic error of primary hyperoxaluria in 1965 [1]. In 1968, Williams and Smith distinguished two disorders among patients with primary hyperoxaluria: most had glycolic aciduria associated with hyperoxaluria, whereas a smaller group excreted L-glyceric acid, “L-glyceric aciduria”, now primary hyperoxaluria type 2 [4, 26]. In 1971 the same group proposed that excess hydroxypyruvate, accumulated through lack of the enzyme that converts it to D-glycerate, stimulates the oxidation of glycolate to oxalate [4].

The enzyme deficiency of PH1 was identified in 1986, when Danpure and Jennings demonstrated absent peroxisomal alanine-glyoxylate aminotransferase (AGT) activity in the liver of patients [27]. In 1989 the same group described a then unprecedented mechanism: in a patient with 8.7% residual activity, AGT was located entirely in the mitochondrion rather than the peroxisome, that is, the disease resulted from an error in the intracellular targeting of the enzyme [1, 28]. AGXT cDNAs were cloned in 1990 by Takada et al. and by Purdue et al., and the gene was mapped to 2q36-q37 in 1991; also in 1990, Purdue et al. found that about one third of patients had an allele carrying the substitutions p.Pro11Leu and p.Gly170Arg, and in 1991 they showed that p.Pro11Leu is necessary and sufficient to create a mitochondrial targeting sequence [1, 10]. The PH2 gene, GRHPR, was cloned in 1999 by two independent groups, Cramer et al. and Rumsby and Cregeen, who identified the first pathogenic variants [11, 29]. PH3 was the last to be defined: in 2010, Belostotsky et al. studied families with calcium oxalate urolithiasis without variants in AGXT or GRHPR, mapped a 6.1 Mb region on chromosome 10 by homozygosity and identified variants in the gene then designated DHDPSL, now HOGA1 [12, 30].

The therapeutic landscape changed in 2020, when lumasiran, a small interfering RNA (siRNA) targeting HAO1 (glycolate oxidase) mRNA, obtained its first marketing authorisation worldwide in the European Union (19 November 2020) and, four days later, in the United States [31]. Nedosiran, an siRNA targeting hepatic lactate dehydrogenase A (LDHA), was approved by the US Food and Drug Administration (FDA) on 29 September 2023 [32]. Until then, the only treatment capable of correcting the PH1 defect was liver transplantation, often combined with kidney transplantation [8].

In this article, the three forms are treated as a class. PH1, which accounts for 70 to 80% of diagnosed cases, is caused by biallelic variants in AGXT; PH2, about 10%, by biallelic variants in GRHPR; and PH3, 10 to 20% depending on the series, by biallelic variants in HOGA1 [8]. Up to 10% of clinically suspected primary hyperoxalurias remain without an identified genetic cause [8], and in the Rare Kidney Stone Consortium (RKSC) registry 11.3% of families with a PH3-like phenotype had no variants in the three genes, which suggests additional heterogeneity [33]. The Orphanet classification groups the three forms under ORPHA:416 (“Primary hyperoxaluria”), within the category “Disorder of glyoxylate metabolism” (ORPHA:308998), with subtypes ORPHA:93598, 93599 and 93600 [13]. Secondary hyperoxalurias (dietary, enteric, toxic), the hyperoxaluria of Zellweger spectrum disorders and idiopathic calcium oxalate urolithiasis fall outside the scope as entities, but are covered in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Glyoxylate and oxalate metabolism

Glyoxylate is a reactive intermediate produced in the liver from glycolate (by peroxisomal glycolate oxidase, encoded by HAO1), from glycine and from mitochondrial hydroxyproline catabolism. Under normal conditions it is detoxified by transamination to glycine by peroxisomal AGT, or reduced to glycolate by cytosolic GR/HPR; whatever escapes these pathways is oxidised to oxalate by LDHA, the terminal step of oxalate synthesis [8, 23]. AGT is synthesised mainly in the liver, translated in the cytosol and imported into the peroxisome by a C-terminal signal; pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, is its essential cofactor, and lysine 209 binds PLP [8, 10]. When AGT is lacking, glyoxylate accumulates and is converted to oxalate, which is poorly soluble, and to glycolate, which has no associated pathology [25].

Understanding these pathways explains the targets of RNA interference treatments. Lumasiran reduces glycolate oxidase, upstream of the PH1 defect, and decreases the glyoxylate available; it therefore acts independently of the AGXT variant, but efficacy is not expected in PH2 or PH3, whose pathways do not pass through that enzyme [21]. Nedosiran reduces LDHA, the final step common to all three types, and was therefore also studied in PH2 and PH3 [34, 35].

2.2. PH1: AGXT and loss-of-function mechanisms

AGXT (2q37.3; MANE transcript NM_000030.3) encodes a 392-amino-acid protein of 43 kDa [9, 10]. More than 260 pathogenic variants are known, distributed across all coding regions, of which about ten are large deletions [8, 16]. p.Gly170Arg is the most frequent in Western populations (28 to 30% of mutant alleles), and c.33dup predominates in other regions [20]. Loss of function results from three classes of mechanism [8]. The first is absence of protein through frameshift or nonsense variants, with nonsense-mediated mRNA decay. The second is misfolding of AGT, which compromises binding of the PLP cofactor and enzyme stability [36]. The third is mistargeting to the mitochondrion. The so-called AGXT minor allele, defined by c.32C>T p.(Pro11Leu), c.1020A>G p.(Ile340Met) and a 74 bp insertion in intron 1, has an allele frequency of 15 to 20% in European and North American populations, about 2% in Japanese and about 50% in patients with PH1 [8, 10]. The p.Pro11Leu substitution creates a cryptic N-terminal mitochondrial targeting sequence with no functional effect on its own; when it is in cis with c.121G>A p.(Gly41Arg), c.454T>A p.(Phe152Ile), c.508G>A p.(Gly170Arg) or c.731T>C p.(Ile244Thr), the enzyme is diverted to the mitochondrion, where it cannot detoxify peroxisomal glyoxylate [1, 8, 36].

The recurrent variants have a known population distribution. c.508G>A p.(Gly170Arg) accounts for about 30% of mutant alleles; c.33dup p.(Lys12GlnfsTer156), also described as c.33_34insC or c.33dupC and located on the major allele, accounts for about 15% of alleles; and c.731T>C p.(Ile244Thr) for about 6% of alleles of all origins, being the predominant variant in patients from Spain and North Africa [10, 16]. In the Canary Islands, 14 of 16 patients studied were homozygous for p.Ile244Thr on a shared haplotype, reflecting a founder effect [10, 37]. In an Italian series of 15 patients, p.Gly170Arg accounted for 30% of alleles and p.Gly158Arg for 13% [10]. In the European infantile oxalosis registry, the most frequent variants were c.33dupC (19%), c.508G>A (13%) and c.731T>C (9.5%) [16].

2.3. Genotype-phenotype correlations and pyridoxine response in PH1

Pyridoxine acts as a chemical chaperone for AGT. Homozygotes for p.Phe152Ile, p.Gly170Arg or p.Ile244Thr treated with pharmacological doses of pyridoxine produce less oxalate and have significantly later ages at first symptoms, diagnosis and kidney failure [8]. Patients with p.Phe152Ile, mostly from Western Europe, had a median age at symptom onset of 19.6 years (0.4–57.9) and at diagnosis of 30.9 years (8.4–59.3), the latest of all genotypes; carriers of p.Gly170Arg had lower oxaluria even without treatment, slower decline in estimated GFR (eGFR), mean age at symptom onset of 14.0 years and at diagnosis of 28.1 years; and p.Ile244Thr homozygotes had a median age at onset of 3.0 years and at diagnosis of 8.0 years, with kidney survival similar to that of p.Gly170Arg homozygotes [8]. The p.Gly41Arg variant has only anecdotal evidence of response [8].

The largest study of determinants of kidney failure analysed 932 patients with PH1 from the OxalEurope registry. Risk was highest in the 175 homozygotes for null variants, unresponsive to vitamin B6, and lowest in the 155 carriers of c.508G>A or c.454T>A, with median ages at kidney failure of 7.8 and 31.8 years, respectively; the 50 c.731T>C homozygotes had better kidney survival than null homozygotes (p=0.003), but other potentially responsive variants were associated with poor outcomes [38]. Nephrocalcinosis tripled the risk of kidney failure (hazard ratio 3.17; 95% CI 2.03–4.94), and oxaluria was higher in patients who progressed (p=0.034), although an intra-individual variation of 41% limits the value of a single measurement [38]. The PNDS summarises that nonsense variants carry a more severe prognosis and that p.Gly170Arg and p.Phe152Ile are associated with slow progression, adult diagnosis and response to B6 [16].

The correlation is only partial. Intrafamilial variability is large: there are siblings with the same genotype and differences of more than 20 years in age at kidney failure, which suggests the involvement of modifier genes and environmental factors such as hydration [8, 16]. Infantile oxalosis is rare in homozygotes for B6-responsive variants and occurs in up to 25% of null homozygotes, but no single variant explains the severe form; the physiologically low GFR of the infant, in the face of high production, appears to contribute [8]. Heterozygotes may have reduced hepatic AGT activity, but have normal oxaluria and do not develop urolithiasis or related kidney disease [8].

2.4. PH2: GRHPR

GRHPR (9p13.2; MANE transcript NM_012203.2) has nine exons spanning about 9 kb and encodes a 328-amino-acid protein that functions as a homodimer, with glyoxylate reductase, hydroxypyruvate reductase and D-glycerate dehydrogenase activities [3, 9]. The protein has a coenzyme-binding domain (residues 107–298), a substrate-binding domain (5–106 and 299–328) and a dimerisation loop (123–149) whose tryptophan 141 projects into the active site of the other subunit [3]. The enzyme is mainly cytosolic and hepatic, but has broader tissue expression than AGT, which has consequences for transplant strategy [3, 16, 25]. All missense variants described give rise to proteins without catalytic activity, so pathogenic variants behave essentially as null [3]. Lack of GR/HPR causes accumulation of glyoxylate and hydroxypyruvate; the latter is reduced to L-glycerate by LDH, which explains the urinary marker [3, 4].

There are founder variants with distinct ethnic distributions. c.103del p.(Asp35ThrfsTer11) has been found only in Caucasian patients of Northern European or American origin, and c.864_865del p.(Val289AspfsTer22), described as c.864delTG, only in Japanese or Chinese patients [4, 9]. c.295C>T p.(Arg99Ter) is another recurrent variant with a possible founder effect [4]. The splicing variant published as c.403_404+2delAAGT corresponds, after normalisation by the 3′ rule, to NM_012203.2:c.404+3_404+6del [3, 9]. The consensus of the European Rare Kidney Disease Reference Network (ERKNet) and OxalEurope attributes 31 to 35% of Caucasian cases to c.103del and identifies c.404+3_404+6del as the most frequent deletion in patients of Asian ancestry, which coexists with the c.864_865del described in Japanese and Chinese series [4, 20]. There is no established genotype-phenotype correlation: in the OxalEurope cohort of 101 patients, with 34 variants (18 novel), kidney outcome did not correlate with genotype [16, 17].

2.5. PH3: HOGA1

HOGA1 (10q24.2; MANE transcript NM_138413.4) encodes mitochondrial 4-hydroxy-2-oxoglutarate aldolase, which cleaves 4-hydroxy-2-oxoglutarate (HOG), an intermediate of hydroxyproline catabolism, into pyruvate and glyoxylate [5, 9]. The paradox of a loss of function that increases oxalate, when the enzyme would produce glyoxylate, has not yet been resolved [3, 5]. The European consensus proposes two hypotheses: accumulated HOG might inhibit GR/HPR, or it might be transported to the cytosol and there converted to glyoxylate by a cytosolic aldolase not yet identified [20]. The variants described are presumed loss-of-function and there is no genotype-phenotype correlation [5]. The splicing variant c.700+5G>T is the commonest in PH3 and accounts for about 50% of mutant alleles according to the PNDS; in the European PH3 patient database, which identified 37 variants, its allele frequency was 46%, followed by c.569C>T p.(Pro190Leu) (8%) and c.944_946del (5%) [5, 9, 16, 20]. In a Chinese series, the splicing variant c.834_834+1delinsTT (published as c.834_834+1GG>TT) accounted for 50% of mutant alleles and c.700+5G>T was absent, showing that the mutational profile differs between populations [9, 20]. In the Ashkenazi Jewish population, c.944_946del p.(Glu315del) accounts for 66% and c.107C>T p.(Ala36Val) for 22% of pathogenic variants [5]. p.Glu315del was found in the homozygous state in four Ashkenazi families in the original description, and other variants emerged in European American, Chinese and consanguineous Tunisian families [6, 12, 30]. Some heterozygotes have increased urinary oxalate precursors, but without hyperoxaluria or a urolithiasis rate higher than that of the general population [5].

2.6. Table of reference variants

The HGVS descriptions were confirmed in VariantValidator on the MANE transcripts (GRCh38) [9]. The numbering “630G-A” used in older texts for p.Gly170Arg corresponds to cDNA numbering predating current conventions [10]. No allelic disorders are known for AGXT, GRHPR or HOGA1 [3, 5, 8]; HOGA1 has, however, been studied as a possible risk factor for idiopathic calcium oxalate urolithiasis [12].

2.7. Renal and systemic pathophysiology

Kidney injury results from urinary supersaturation with calcium oxalate. Crystals damage the tubular epithelium, aggregate into calcium oxalate monohydrate (whewellite) stones and deposit in the interstitium; obstruction, infection, repeated urological procedures and nephrocalcinosis progressively lower GFR [8, 16]. Supersaturation depends not only on oxalate but also on calcium, citrate, magnesium, pyrophosphate, glycosaminoglycans and urinary proteins, which underpins the use of crystallisation inhibitors [16]. With GFR below 30 mL/min/1.73 m², production exceeds elimination and plasma oxalate exceeds the calcium oxalate supersaturation threshold, estimated at 30 to 45 µmol/L, with tissue deposition [8]. Bone is the largest reservoir, followed by vessels and the heart [8, 16]. In the myocardium, crystals cause hypertrophic and restrictive cardiomyopathy and, in the conduction system, atrioventricular block [8, 39]. Mobilisation of these deposits after transplantation or the start of effective treatment may last months to more than five years and exposes the transplanted kidney to renewed crystallisation [8].

3. Clinical Spectrum and Manifestations by System

3.1. Common syndromic description

The three primary hyperoxalurias share a pathophysiological sequence: hyperoxaluria present from birth, calcium oxalate crystalluria, recurrent urolithiasis and nephrocalcinosis, progressive kidney injury and, when GFR falls below about 30 mL/min/1.73 m², systemic accumulation of oxalate [8, 16]. The 2023 ERKNet/OxalEurope consensus places this threshold between 30 and 40 mL/min/1.73 m² and estimates that the combination of intratubular and interstitial deposits, chronic tubulointerstitial inflammation and stone obstruction leads to kidney failure in more than 70% of patients with PH [20]. The disease may present at any age, from the prenatal period to beyond 60 years, but most patients have their first symptom before the age of 5; the median age at detection lies between 15 and 20 years, and in PH1 half of patients already have advanced kidney failure at diagnosis [16]. Severity decreases, on average, from PH1 to PH2 and from PH2 to PH3; the PNDS describes PH2 as less severe and more slowly progressive and PH3 as even less severe, although the initial presentation may be indistinguishable between the three types [16].

The natural history described in the cohorts that follow corresponds mostly to patients treated with conservative measures (hydration, citrate, pyridoxine) and, in part, with transplantation, but without RNA interference. Outcomes on lumasiran or nedosiran are still limited to trials with a maximum follow-up of 5 years and to real-world cohorts, covered in section 7, and cannot be read as natural history.

3.2. PH1: forms by age at presentation

The presentation of PH1 falls into three age groups with distinct profiles [8]. About 10% of patients present in the first year of life, with marked nephrocalcinosis, variable urolithiasis, advanced chronic kidney disease (CKD) or kidney failure and early oxalosis; about 70% present between 1 and 17 years, with urolithiasis as the dominant manifestation, less frequent nephrocalcinosis and normal to moderately reduced kidney function; and about 20% are diagnosed only in adulthood, mainly through urolithiasis, with nephrocalcinosis more frequent when advanced CKD is already present [8]. The infantile form accounts for up to 10% of cases in Europe and the United States, but up to 35% in regions with frequent consanguinity [8].

Source: GeneReviews PH1, Table 4 [8].

3.2.1. Infantile oxalosis

Infantile oxalosis is defined as CKD stage 5 on dialysis (5D) caused by PH before 1 year of age and has been described only in PH1 [20]. More than half of the children with PH1 diagnosed in the first year are already in CKD stage 5 at diagnosis; the commonest manifestations are feeding difficulties and failure to thrive, sometimes seizures due to electrolyte disturbances, and a high proportion have significant nephrocalcinosis or urolithiasis [20]. Kidney failure may appear at 4–6 months and typically occurs before 12 months; infants who are not on dialysis at diagnosis frequently progress to kidney failure within a few months despite optimal supportive treatment [8]. In the OxalEurope registry, 95 patients born between 1980 and 2018 reached kidney failure at a median age of 0.4 years (0.3–0.5); four had been diagnosed by family screening and progressed nonetheless, and 11 had biallelic missense variants associated with pyridoxine response [40]. Systemic oxalosis was documented in 54 of the 56 patients screened (96%), with retinal deposits in 43 of 54, bone deposits in 34 and cardiac deposits in 11, and nephrocalcinosis was present in 66 of 81 [16, 40]. Twenty-seven of 89 patients died (30%), at a median age of 1.4 years, and 5-year survival was 69%; mortality fell from 54% (14/26) in those born before 2000 to 21% (13/63) in those born afterwards [16, 40]. The first transplant took place at 1.7 years (1.3–2.9), in 42 cases as combined liver-kidney transplantation and in 23 as liver transplantation within a sequential strategy, with similar survival between the two strategies [40]. There was intrafamilial phenotypic variability in 14 families of patients with infantile oxalosis [40].

3.2.2. Childhood and adolescent form

In patients diagnosed in childhood or adolescence, the first manifestations appear before the age of 10 in most and in 85 to 90% by age 20; in a large European study, the median age at onset was 4.0 years and at diagnosis 8.0 years [8]. Symptoms are haematuria, dysuria, abdominal or flank pain, urinary tract infections and passage of stones or gravel; in infants and young children the symptoms of urolithiasis are non-specific (vomiting, chronic abdominal pain, crying, restlessness) and growth is normal between episodes [8, 16]. Kidney function at diagnosis is normal or mildly to moderately reduced and declines slowly, but the decline may accelerate with bilateral obstruction, repeated stone removal procedures or dehydration [8]. Most avoid kidney replacement therapy until adulthood, but kidney failure may occur before the age of 40; higher oxaluria and nephrocalcinosis are associated with greater risk [8, 38, 41]. In the French cohort of 155 patients with PH1 from 129 families (1993–2008), the median age was 4 years at first manifestation and 7.7 years at diagnosis, consanguinity was present in 46% and 10% were diagnosed by recurrence in the kidney graft; cumulative kidney survival was 81% at 10 years, 59% at 20, 41% at 30 and 10% at 50 years, and patient survival was 95% at 10 years, with the infantile form as the only factor associated with mortality (relative risk 5.3; 95% CI 1.6–18.2) [16, 42]. p.Gly170Arg was present in 26% of patients and was associated with a better course [42]. Among 54 European patients with PH1 who started kidney replacement therapy in childhood or adolescence between 2000 and 2009, 5-year survival after that start was 83%, better than before 2000, particularly in those under 2 years, but lower than that of children with other nephropathies [43].

3.2.3. Adult form

About 20% of patients are diagnosed in adulthood, mainly through urolithiasis; a focused history often reveals earlier symptoms or urological procedures in which PH1 was not considered [8]. The presentation may be acute kidney injury due to bilateral obstruction or after stone removal, or a calcium oxalate monohydrate crystal nephropathy triggered by dehydration or surgery [8, 16]. PH1 remains undiagnosed in 20 to 50% of adults until advanced CKD or kidney failure, and in about 10% the diagnosis is made only after recurrence in the transplanted kidney, with oxalate crystals on graft biopsy and frequently graft loss [8]. Some patients remain free of manifestations until the sixth decade, and GFR at diagnosis is lower in adults than in children [8]. In the French national cohort of genetic diagnoses between 2015 and 2019 (52 patients, 34 children and 18 adults), 23% were on dialysis at diagnosis, renal colic was the initial manifestation in 79% of adults with PH1 and 17% of children, and the median diagnostic delay was 1.2 years (0.1–3.0) in children and 30 years (17–36) in adults (p<0.0001) [44]. In the Netherlands, 10 of 17 patients diagnosed as adults were already in end-stage kidney disease, against 9 of 40 diagnosed in childhood [16, 45].

3.2.4. Determinants of progression

In the OxalEurope registry of 932 patients with PH1, the median age at kidney failure was 7.8 years in homozygotes for null variants and 31.8 years in carriers of c.508G>A or c.454T>A; nephrocalcinosis was associated with a 3.17-fold higher risk of kidney failure (95% CI 2.03–4.94) [38]. Nephrocalcinosis is present on the first imaging study in 30% of patients with preserved kidney function [8]. The number of stones did not correlate with kidney function or with the risk of kidney failure, unlike nephrocalcinosis, adjusted for the number of stones [20, 41].

3.3. PH2

PH2 typically begins in childhood, and patients diagnosed later often report symptoms since childhood; diagnosis is often delayed by years [3]. The manifestations are haematuria, renal colic and obstruction by calcium oxalate stones; nephrocalcinosis is less frequent than in PH1 [3]. The OxalEurope cohort of 101 patients (75 families, 11 countries; median follow-up 12.4 years) showed a median age of 3.2 years at first symptom and 8.0 years at diagnosis in index cases; urolithiasis was the presentation in 82.8%, nephrocalcinosis was present in 35.1% and recurrent urinary tract infections in 32.1% [16, 17]. Forty-five of 89 patients had CKD stage 2 or higher and 22 reached stage 5, at a median of 40.4 years; median kidney survival was 43.3 years, systemic oxalosis was described in 4 of the patients in end-stage kidney disease and 7 of the 22 died [17]. Kidney outcome did not correlate with genotype, biochemistry or initial nephrocalcinosis [17]. Although patients with PH2 are as likely to have nephrocalcinosis and urolithiasis in the first year of life as patients with PH1, progression to CKD stage 5 does not usually occur before the age of 15 [20]. A series of 8 patients from three Saulteaux-Ojibway families in north-western Ontario showed a mild spectrum, with four patients symptomatic in childhood and four asymptomatic [4].

After kidney failure, oxalosis in PH2 affects bone, bone marrow, joints, retina and myocardium, and calcified nodules in the fingers have been described; radiography shows symmetrical transverse translucent bands with sclerotic margins at the ends of the long bones and, later, cystic rarefaction [3]. The clinical consequences are bone pain, pathological fractures, erythropoietin-resistant anaemia, retinopathy and maculopathy, heart block, cardiomyopathy, synovitis, ischaemia and skin ulcers, periodontitis and hypothyroidism [3].

3.4. PH3

PH3 presents with recurrent calcium oxalate urolithiasis from childhood or adolescence, with onset typically before the age of 5 and a median age at presentation of 2 to 3 years, sometimes only in adulthood [5]. Symptoms are microscopic or macroscopic haematuria, urinary frequency, dysuria and pain; the first imaging study shows a median of four stones, and symptomatic stone events may recur until the sixth decade, often with surgery [5]. Detection may be incidental [5]. In the OxalEurope registry (95 patients, 74 followed for a median of 6 years), the median age was 1.9 years at first symptom and 6.3 years at diagnosis; urolithiasis was present in 70% of children and 50% of adults, citraturia was normal, hypercalciuria rare, and 21.4% had CKD stage 2 or higher at last follow-up [19]. Nephrocalcinosis affects 7 to 10% of patients, with lower estimated GFR (eGFR) in these cases, and 21.5% of infants under 1 year [5, 16]. Oxaluria did not differ from that of patients with pyridoxine-unresponsive PH1 or from that of patients with PH2 (medians of 1.37, 1.40 and 1.16 mmol/1.73 m²/24 h, respectively) [19].

Kidney failure is exceptional. After the age of 40, the prevalence of CKD stage 3 or higher exceeds that expected for age, but kidney failure by age 40 affects about 3% of patients [5]. The three patients with PH3 described in kidney failure had additional factors: an 8-year-old child with multiple procedures and obstruction, a 33-year-old patient with bladder dysfunction and a 78-year-old man with 30 years of urolithiasis and unilateral nephrectomy for clear cell carcinoma [5]. Systemic oxalosis has not been described, but the number of patients with advanced CKD is small [5].

3.5. Comparison of the three types

The North American Rare Kidney Stone Consortium (RKSC) registry compared 384 patients with PH1, 51 with PH2 and 62 with PH3 [18]. The median age at first symptoms was 2.7 years in PH3, 4.9 in PH1 and 5.7 in PH2; nephrocalcinosis at diagnosis was present in 7% of patients with PH3, and urolithiasis in 89% [18]. Median oxaluria was lowest in PH3 (1.1 versus 1.6 and 1.5 mmol/1.73 m²/24 h; p<0.001), and calciuria highest (112 versus 51 and 98 mg/1.73 m²/24 h), whereas the number of stone events per decade was similar in the three types; at age 40, 97% of patients with PH3, 36% with PH1 and 66% with PH2 were free of kidney failure [18]. In the European series, by contrast, oxaluria was similar in the three types [8, 19].

Source: GeneReviews PH1 (Table 5) and PH3 (Table 3), based on Singh et al. [5, 8, 18]. The proportions refer to diagnosed patients; population analyses suggest that the genomic prevalence of PH3 is close to that of PH1, so these proportions reflect underdiagnosis or incomplete penetrance [8, 33].

3.6. Systemic oxalosis by organ

When GFR falls below 30 mL/min/1.73 m², daily oxalate production exceeds clearance, plasma oxalate rises rapidly and deposits in the kidney, bone, retina, myocardium, vessels, bone marrow, subcutaneous tissue, peripheral nerves and synovium; in most patients on conventional dialysis, oxalosis progresses and leads to death [8]. The PNDS stresses that most of the accumulation is in bone and the cardiovascular system, and that the thyroid is the main endocrine organ affected [16].

Cardiac involvement may carry its own prognostic weight. In a study of 1108 patients with type 2 diabetes on haemodialysis and without PH, the median plasma oxalate was 42.4 µmol/L, and values in the upper quartile (>59.7 µmol/L) correlated with NT-proBNP and with the risk of sudden cardiac death, suggesting that oxalate overload has cardiovascular effects even outside PH [16, 48]. Most manifestations of oxalosis regress slowly after liver-kidney transplantation, and cardiac involvement is at least partially reversible after liver and kidney transplantation [8, 39]. In a single-centre retrospective cohort, the long-term complications of systemic oxalosis in children included osteopathy with fractures, retinopathy, cardiomyopathy and hypothyroidism [46].

3.7. Recurrence after kidney transplantation

In PH1, the enzyme defect remains in the liver after isolated kidney transplantation, and hyperoxaluria persists [16]. The presentation may be early post-transplant acute kidney injury, with marked calcium oxalate deposits on biopsy (acute oxalate nephritis); in retrospect, most of these patients had a history of urolithiasis [16]. Diagnosis of PH after kidney transplantation is associated with an early graft loss rate above 75% and is more common in resource-limited countries [20].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

PH should be considered at any age in the presence of recurrent calcium oxalate urolithiasis or nephrocalcinosis, particularly when there is progressive CKD or a family history of urolithiasis and kidney disease [8, 20, 24]. The French PNDS formulates the rule more strictly for paediatrics: every urinary stone and every case of nephrocalcinosis in a child requires a full aetiological work-up that includes testing for PH [16]. The European consensus algorithm proposes measuring urinary oxalate in all patients under 18 years with stones or nephrocalcinosis and eGFR above 30 mL/min/1.73 m², in all adults with more than two stone episodes or with nephrocalcinosis and eGFR above 30, and plasma oxalate in all patients with eGFR below 30 and nephrocalcinosis or stones [20]. The 2024 Oxalosis and Hyperoxaluria Foundation (OHF) best practices broaden the criteria in adults: testing is warranted by a calcium oxalate stone in any child, recurrent stones or a first stone before the age of 21 in adults, nephrocalcinosis, a relative with childhood urolithiasis, recurrent urolithiasis or unexplained CKD, a relative with PH and detection of calcium oxalate crystals under polarised light in a kidney or other tissue biopsy [24]. Younger age at onset, greater stone burden and nephrocalcinosis increase the likelihood of a genetic cause [24].

The PNDS considers that the presence of any one of the adult criteria is sufficient to refer the patient to a nephrology team specialised in urolithiasis [16]. The absence of a family history does not exclude the diagnosis, because inheritance is recessive and siblings may be discordant [8]. All patients with hyperoxaluria not attributable to a secondary cause, and all patients with CKD and suggestive findings, should undergo genetic testing [8]. In resource-limited countries, the European consensus recommends screening for PH in all patients on dialysis or in CKD stage 5 of unknown cause, to avoid diagnosis after kidney transplantation [20].

4.2. Emergency signs

Situations requiring immediate action are bilateral obstruction or obstruction of a solitary kidney, obstructive pyelonephritis and anuria, which require urgent urinary diversion by double-J stent or nephrostomy before treatment of the stones [16]. Dehydration due to gastroenteritis, pre-anaesthetic fasting or vomiting in pregnancy may trigger acute kidney injury due to crystal nephropathy and requires early intravenous hydration [8, 16]. Urological procedures, particularly stone removal procedures, may precipitate acute kidney injury [8, 16]. In infants, kidney failure with raised plasma oxalate is an emergency, because kidney failure and oxalosis may set in within weeks [8, 40]. After kidney transplantation, a rise in creatinine in the first weeks may correspond to acute oxalate nephropathy of the graft [16].

4.3. Presymptomatic diagnosis and newborn screening

Genetic testing of a patient's siblings is indicated at any age, even if they are asymptomatic, because intrafamilial variability is large, asymptomatic biallelic carriers are at increased risk of urolithiasis and kidney injury and effective treatments exist [5, 8, 16, 50]. Patients identified by family screening have fewer manifestations at diagnosis than those identified on clinical grounds, but are not free of risk [50]. The PNDS raises the question of preventing infantile oxalosis with early RNA interference in screened families [16].

There is no routine biochemical newborn screening for PH. The disease is included in research programmes of genomic newborn screening, such as Early Check (NCT03655223, United States), Baby Detect (NCT05687474, Belgium) and a genetic screening study for cystinosis and PH (NCT05843851), whose results for PH are not published in the sources consulted [51].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The diagnosis of each type of PH is established in a patient with suggestive findings by identification of biallelic pathogenic or likely pathogenic variants in AGXT (PH1), GRHPR (PH2) or HOGA1 (PH3) [3, 5, 8, 16]. The European consensus considers genetic testing the reference standard for all three types and recommends it in all patients with high clinical or biochemical suspicion (statement 1, grade A), because confirmation and typing determine treatment: only PH1 responds to pyridoxine and to the approved RNA interference agents, and PH1 has a worse prognosis [20]. Testing should be performed as early as possible and, in patients with eGFR below 30 mL/min/1.73 m², within 30 days [20]. Identification of two variants of uncertain significance (VUS), or of one pathogenic variant and one VUS, neither establishes nor excludes the diagnosis [8]. The French PNDS states that liver biopsy no longer has a place in diagnosis [16]; the 2017 GeneReviews for PH2 still proposed it when genetic testing identified zero or one variant, with measurement of glyoxylate reductase activity in a sample of about 20 mg frozen immediately, and advised against leucocytes [3].

5.2. Urinary oxalate

24-h urinary oxalate, with measurement of urinary creatinine to validate the collection, is the initial test in patients with preserved kidney function (statement 3, grade A) [16, 20]. Urine should be collected into acid or acidified in the laboratory to pH below 2, to dissolve crystals and preserve oxalate; non-acidified collections should be acidified and homogenised before aliquoting, otherwise results will be falsely low, and samples with pH above 8 are unsuitable, because in vitro oxalogenesis may occur [8, 20]. Acidification in the laboratory is acceptable up to 24 h after collection if the sample is kept at 4 °C (statement 6) [20]. In young children, or when a 24-h collection is impracticable, the oxalate/creatinine ratio in a spot sample is used, interpreted against age-specific reference values, because the ratio falls rapidly in the first year and stabilises at around 5 years (statements 4 and 7) [20]. At least two measurements above the upper limit are required to establish hyperoxaluria (statement 5, grade B), preferably three if results are equivocal; excluding very oxalate-rich foods in the preceding 24 h may clarify borderline cases [20]. Urinary oxalate above 1 mmol/1.73 m²/24 h is strongly suggestive of PH, but enteric causes, whose values overlap, must be excluded before further investigation [20]. The PNDS sets the threshold for hyperoxaluria at 0.45 mmol/24 h and notes that types 1 and 2 often exceed 0.75 mmol/24 h [16]. During the diagnostic collection the patient should not be taking pyridoxine or high-dose ascorbic acid supplements; high-dose vitamin C may cause marked hyperoxaluria, and urinary oxalate should be repeated after it has been stopped [5, 16].

The two reference tables are not identical: that of the European consensus, reproduced in the PNDS, gives ranges and distinguishes sex in adults, whereas that of GeneReviews gives upper limits derived from other series [8, 16]. The OHF best practices adopt the same mmol/mmol limits as GeneReviews and set the diagnostic threshold for 24-h urinary oxalate at 0.5 mmol (45 mg)/1.73 m², slightly above the PNDS 0.45 mmol/24 h [16, 24]. Preterm infants, especially on parenteral nutrition with amino acids, have higher ratios than term newborns, and hyperoxaluria may also occur with total parenteral nutrition or high gelatine intake [8, 20]. Intra-individual biological variation is high in healthy individuals (43% for 24-h urinary oxalate and 79% for the spot ratio) and, in patients with PH, about 14% for 24-h urinary oxalate, with a reference change value of 32%; a fall of at least one third is therefore required to establish a response to treatment [20]. In the OxalEurope PH2 registry, 9.7% of spot samples were normal against less than 4% of 24-h collections, and the intra-individual variation of 24-h urinary oxalate was 34.1% [17]. In PH3, urinary oxalate is more variable and may intermittently lie between 0.4 and 0.7 mmol/1.73 m²/24 h, which requires repeated measurements [5].

5.3. Specific urinary metabolites

Measurement of glycolate (PH1), L-glycerate (PH2) and HOG and DHG (PH3) in the same sample may guide genetic testing (statement 9, grade B), but it is available only in specialised laboratories, and normal values do not exclude the diagnosis [16, 20]. Urinary glycolate is raised in about 75% of patients with PH1, but it is not specific: it varies with diet and is markedly raised in glycolate oxidase deficiency, a generally benign condition, and in ethylene glycol poisoning [20, 52]. L-glycerate may be missed on organic acid screening, and the specific assay, with 100% sensitivity, is preferable [3, 20, 53]. HOG is unstable and may give false negatives, whereas DHG has 100% sensitivity for PH3 [20]. Liquid chromatography-tandem mass spectrometry methods exist that simultaneously screen for the urinary metabolites of all three types, but definitive diagnosis still requires genetic testing [54]. There are no international calibrators for these analytes, and results are interpreted against local reference ranges [20]. In any case, elevation of these metabolites must be confirmed by genetic testing (statements 10 to 12, grade A) [20].

5.4. Plasma oxalate

Plasma oxalate has diagnostic value only with eGFR below 30 mL/min/1.73 m² (CKD stage 4 or higher; statement 13, grade A), a situation in which urinary excretion no longer reflects production [16, 20]. A normal value with normal kidney function does not exclude PH [16]. Plasma oxalate rises with falling GFR in any nephropathy, and patients on dialysis without PH may have mean values of 50 to 60 µmol/L, so interpretation must compare the patient with populations with the same degree of kidney failure rather than with healthy individuals (statement 14) [16, 20]. GeneReviews considers values above 20 µmol/L in advanced CKD compatible with PH1 and values above 50 µmol/L strongly suggestive, and in PH2 values often exceed 50 µmol/L when GFR falls below 20 mL/min/1.73 m² [3, 8, 55]. On dialysis, patients with PH1 often have values above 100 µmol/L [8]. In PH3 with CKD stages 1 to 3A, plasma oxalate may be slightly raised (1.6–20 µmol/L) [5]. The measurement is technically difficult: results vary between laboratories and methods (ion chromatography coupled with mass spectrometry gave values 33% lower than gas chromatography-mass spectrometry), there is no external quality control material, and oxalate may fall by half during a haemodialysis session; longitudinal follow-up should always be performed in the same laboratory [16, 20]. In patients with PH not on dialysis, plasma oxalate is normal or slightly raised while eGFR remains above about 40 mL/min/1.73 m² and rises rapidly below that value; the OHF recommends stopping any vitamin C supplement in the 24 h preceding sampling and, in patients on dialysis, sampling after the longest interdialytic interval [24].

5.5. Stone analysis and crystalluria

Morphoconstitutional analysis of the stone by infrared spectrophotometry is a key element of the aetiological diagnosis [16]. PH1 stones are of almost pure whewellite (calcium oxalate monohydrate) and have a characteristic morphology, subtype Ic of the Daudon classification: very pale colour, from creamy white to light yellowish-brown, a “budding” surface and a poorly organised section [16, 20]. In the urolithiasis laboratory of the Assistance Publique-Hôpitaux de Paris, 123 of 128 stones from patients with PH (96.1%) had Ic morphology, a morphology found in only 0.1% of stones outside this context [16]. Ic stones exceeding about 10 mm may acquire an organised periphery similar to that of subtype Ia, but of unusually pale colour, so a report of an Ia stone does not exclude PH [16]. PH2 and PH3 stones often contain mixtures of calcium oxalate and phosphate and cannot be distinguished from those of idiopathic stone formers; in these types, stone burden and rate of recurrence are more useful indicators [20]. Enteric urolithiasis produces whewellite stones of similar morphology (subtype Ie) [16]. During renal colic, urine should be strained with a dedicated filter or, failing that, with a gauze or coffee filter, and all passed stones should be analysed, even if previous analyses exist [16].

Crystalluria is studied in the first morning urine, never in 24-h urine, examined within two hours of voiding and kept above 20 °C [16]. Whewellite crystalluria should raise suspicion of hyperoxaluria, and more than 200 crystals/mm³, particularly without weddellite, should prompt systematic testing for PH; specificity is higher in young children than in adults [16, 20]. Negative crystalluria, or fewer than 200 crystals/mm³, does not exclude PH [16]. In the European consensus, statement 8, which suggests including crystalluria in the assessment, was the only one without 70% panel agreement, owing to lack of availability and experience; it was retained with the note that crystalluria does not replace genetic testing or urinary biochemistry [20].

5.6. Genetic testing

GeneReviews proposes two equivalent strategies: a nephrology panel including AGXT, GRHPR, HOGA1 and all genes for monogenic urolithiasis and nephrocalcinosis, or exome sequencing with initial analysis limited to those genes [8]. If the phenotype is suggestive and only one or no variant is identified, genome sequencing makes it possible to look for deep intronic and structural variants [8]. In the case of a VUS, family segregation and, exceptionally, enzyme activity in a liver biopsy may clarify the classification [8]. In France, cases with zero or one variant are discussed with a specialised centre or at the national multidisciplinary urolithiasis meeting of the ORKiD filière [16].

These percentages describe the proportion of known variants that each method detects and not the clinical sensitivity of the test, that is, the probability of finding two variants in a patient with clinically evident PH. In the RKSC registry, 11.3% of families with a PH phenotype had no variants in the three genes, and up to 10% of clinically suspected PH remain without a genetic cause [8, 33]. A negative result with compatible phenotype and biochemistry therefore does not exclude an inherited hyperoxaluria.

The report should state the gene, the versioned reference transcript (NM_000030.3, NM_012203.2 or NM_138413.4), the HGVS description at cDNA and protein level, zygosity, the phase of the variants when relevant and the class according to the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria [8, 9]. In PH1, the report has direct therapeutic implications: the presence of p.Gly170Arg, p.Phe152Ile or p.Ile244Thr in the homozygous state or with another variant predicts response to pyridoxine, and the minor allele haplotype (c.32C>T) in cis modulates the effect of several missense variants [8, 20]. Parental testing is needed to confirm the trans configuration. If only one parent is a carrier, a de novo variant in the proband or parental mosaicism is possible; apparent homozygosity may correspond to an undetected deletion on the other allele or to uniparental isodisomy, and a case of PH1 due to telomeric maternal isodisomy of chromosome 2, homozygous for c.33dup, has been published [8].

5.7. Diagnostic algorithm

Source: ERKNet/OxalEurope consensus, Figure 2 [20].

The OHF algorithm (Figure 1 of the 2024 best practices) separates two entry points [24]. In the patient with urolithiasis and normal kidney function, hyperoxaluria is defined as urinary oxalate above 0.5 mmol (45 mg)/1.73 m²/24 h or an oxalate/creatinine ratio above normal for age, confirmed by a repeat measurement and, if available, by measurement of glycolate, L-glycerate and HOG; before genetic testing, secondary causes are sought (malabsorption, gastrointestinal disease, a diet very rich in oxalate and low in calcium, prematurity), which, if present, are assessed and treated [24]. In the patient with CKD stages 3 to 4 or on dialysis and with stones, calcium oxalate tissue deposits or nephrocalcinosis, plasma oxalate is measured and, if there is residual diuresis, 24-h urinary oxalate (or the oxalate/creatinine ratio in young children); urinary oxalate above the threshold and/or plasma oxalate above 20 µmol/L lead directly to testing of AGXT, GRHPR and HOGA1 [24]. Because oxalate is eliminated by the kidney, urinary oxalate may fall below 0.5 mmol/1.73 m²/24 h when GFR is very reduced, without this excluding the disease [24]. Without biallelic variants, the algorithm proposes continuing clinical management of the hyperoxaluria and considering research studies of new genetic causes [24]. The two algorithms converge on mandatory genetic confirmation; they differ in the interpretation of plasma oxalate (a threshold of 20 µmol/L as the trigger for testing in the OHF; comparison with patients with the same degree of kidney failure in the European consensus) and in empirical treatment, which the European consensus starts in all suspected patients and the OHF makes explicit mainly for pyridoxine in patients with rapidly progressive CKD [20, 24].

5.8. Initial assessment after diagnosis

The initial assessment includes kidney imaging (ultrasound; low-dose non-contrast computed tomography (CT) if ultrasound is equivocal, because a normal ultrasound does not exclude nephrocalcinosis), 24-h urine for oxalate, calcium, citrate, pH, volume and supersaturation, plasma oxalate when eGFR is below 30, eGFR by creatinine, urea and cystatin C, a genetics clinic appointment and information about patient associations [8, 16]. The PNDS recommends thyroid, ophthalmological (fundoscopy) and cardiological (echocardiogram and electrocardiogram) assessment at diagnosis in all patients, and the European consensus recommends eye examination and echocardiography at diagnosis (statements 39 and 40) [16, 20]. In patients with CKD stage 3b or higher, the assessment adds bone imaging, a full blood count to detect erythropoietin resistance and an electrocardiogram [8]. Bone densitometry is of no value according to the PNDS [16].

5.9. Prenatal and preimplantation diagnosis

Prenatal diagnosis of PH1 was historically made by AGT activity in fetal liver biopsy (Danpure et al., 1988) and by metabolites in amniotic fluid, and was later replaced by DNA analysis [1]. Currently, once the familial variants have been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are technically possible for all three types [3, 5, 8]. In France, the PNDS allows prenatal or preimplantation diagnosis in families at risk of PH1, after discussion at a multidisciplinary prenatal diagnosis centre [16]. The clinical case in section 10 illustrates a diagnosis at 11 weeks by chorionic villus sampling followed by treatment from birth [56].

6. Differential Diagnosis

The differential diagnosis has three levels: distinguishing between the three types of PH, distinguishing PH from secondary hyperoxaluria and distinguishing PH from the other monogenic causes of urolithiasis and nephrocalcinosis [8, 25]. Stone analysis and the urinary stone-risk profile (volume, oxalate, calcium, magnesium, citrate, phosphate, sodium and urate) guide the work-up; confirmation is genetic [3, 20].

6.1. Comparative table

Sources: [3, 5, 8, 16, 20, 25, 52, 57, 58]. AR, autosomal recessive. The Daudon morphoconstitutional classification associates subtype Ic with primary hyperoxaluria, Ie with enteric hyperoxaluria, Ia with intermittent hyperoxaluria (fluid deficit, foods rich in oxalate or hydroxyproline, low calcium) and subtypes IIa and IIb with idiopathic hypercalciuria [16].

6.2. Between the three types of PH

The three types have a similar initial presentation, and age, nephrocalcinosis or urinary oxalate do not reliably distinguish the type in an individual patient [16, 19]. Urinary metabolites provide guidance (glycolate in PH1, L-glycerate in PH2, HOG and DHG in PH3), but a normal value of each does not exclude the corresponding type, and definitive diagnosis requires genetic testing [8, 20]. In PH3, citraturia and calciuria are usually normal, whereas in PH1 they are often lower [8, 18]. The distinction has immediate consequences: pyridoxine and the approved RNA interference agents apply only to PH1, and the transplant strategy differs between PH1 and PH2 [16, 20].

6.3. Secondary hyperoxaluria

Enteric hyperoxaluria is the condition closest to PH in clinical and biochemical manifestations. Unabsorbed fat binds calcium in the colonic lumen, leaving oxalate free to be absorbed, and fatty acids and bile salts increase the permeability of the colonic mucosa [8]. Urolithiasis is active and recurrent, urinary oxalate usually lies between 0.5 and 1 mmol/24 h and may overlap with that of PH in short bowel syndrome, whewellite crystalluria is abundant and the stones have a morphology close to type Ic (designated Ie); CKD due to crystal nephropathy is possible, but radiological nephrocalcinosis is rarer [8, 16]. In bariatric surgery, Roux-en-Y gastric bypass carries a higher risk than gastric banding [8]. The European consensus requires exclusion of enteric causes (chronic pancreatitis, cystic fibrosis, inflammatory bowel disease, bariatric surgery) before proceeding to metabolic or genetic investigation [20].

Dietary hyperoxaluria results from an unbalanced diet combining oxalate-rich foods (nuts, tea, coffee, chocolate, spinach, rhubarb, beetroot, star fruit, peanut butter) with little calcium, which favours intestinal absorption of oxalate [3, 16]. Diet contributes 24 to 53% of urinary oxalate in healthy individuals [3]. High-dose vitamin C, alone or in multivitamin supplements, may cause marked hyperoxaluria; cases with 4 g/day have been described [3, 16]. Excessive consumption of gelatine products, rich in hydroxyproline, increases hepatic oxalate synthesis [16, 20]. In classic galactosaemia treated with soy formula, hyperoxaluria with stones has been described [59]. The PNDS points out that more than half of kidney stones are associated with hyperoxaluria and that, without warning signs (severe and recurrent urolithiasis, onset in childhood, history in siblings, abnormal kidney morphology), most are of dietary origin [16].

Ethylene glycol poisoning causes marked hyperoxaluria, glycolic aciduria and acute kidney injury; urinary glycolic acid without an inherited disease should suggest this poisoning, and the secondary causes of increased urinary oxalic acid are malabsorption, a diet rich in rhubarb and spinach, pyridoxine deficiency, ethylene glycol and ascorbic acid [8, 52].

6.4. Idiopathic calcium oxalate urolithiasis

Calcium oxalate is the component of about 80% of stones [8]. In idiopathic urolithiasis, urinary oxalate is lower (generally below 0.6 mmol/day), varies between collections and is often accompanied by hypercalciuria; the stones are type Ia or mixed with weddellite [8, 16]. HOGA1 has been studied as a possible risk factor for idiopathic urolithiasis [12], but heterozygotes for HOGA1 variants have neither hyperoxaluria nor a higher urolithiasis rate than the general population [5].

6.5. Peroxisomal disorders

In the Zellweger spectrum, hyperoxaluria is frequent: in a Dutch cohort of 31 patients, 19 of the 23 tested (83%) had hyperoxaluria, often with hyperglycolic aciduria, five had urolithiasis, three nephrocalcinosis and one kidney failure [8]. Neurodevelopmental delay, retinopathy, deafness and liver dysfunction distinguish these disorders from PH1 [8]. Oxalate accumulates in plasma and urine and forms calcium oxalate stones; abundant hydration and oral citrate are recommended [58].

6.6. Other monogenic causes of urolithiasis and nephrocalcinosis

Dent disease and familial hypomagnesaemia with hypercalciuria and nephrocalcinosis cause marked nephrocalcinosis and CKD, but with hypercalciuria and normal urinary oxalate [8]. In CYP24A1-related infantile hypercalcaemia, hypercalcaemia in infancy may be severe, renal cysts are frequent and CKD is common [8]. In hereditary hypophosphataemic rickets with hypercalciuria (SLC34A3), renal phosphate wasting, hypophosphataemia and raised 1,25(OH)₂D cause hypercalciuria and rickets or osteomalacia; monoallelic SLC34A3 variants are enriched in calcium stone formers [8]. Adenine phosphoribosyltransferase deficiency produces radiolucent or intermediate-density stones and CKD due to crystal nephropathy, with normal urinary oxalate [8]. Distal renal tubular acidosis, cystinuria and xanthinuria complete the differential of early-onset hereditary urolithiasis, and stone analysis distinguishes most of them [3, 25]. In glycogen storage disease type I, hypocitraturia and hypercalciuria favour calcium oxalate precipitation, and oral citrate is preventive [57].

6.7. Nephrocalcinosis of prematurity

Newborns of less than 28 weeks' gestation may have nephrocalcinosis and urolithiasis, favoured by urinary oxalate higher than that of term newborns, by hypercalciuria and by hypocitraturia [8]. Because PH3 causes stones in infants and young children, it may be confused with nephrocalcinosis of prematurity [5]. Persistence or progression of nephrocalcinosis and urinary oxalate raised for corrected age justify genetic testing.

7. Treatments and Risk Management Strategies

7.1. Objectives and organisation of care

Treatment has three objectives: to increase the solubility of urinary calcium oxalate continuously, to reduce endogenous oxalate production and, when kidney function is already compromised, to prevent systemic deposition [16]. Conservative treatment (hyperhydration, a crystallisation inhibitor and a therapeutic trial of pyridoxine) should start as soon as the diagnosis is suspected, before genetic confirmation (European consensus statement 15, grade B) [16, 20]. The targets proposed by the PNDS are a urinary oxalate concentration below 0.4 mmol/L, a urinary calcium concentration below 3.8 mmol/L and 24-h urinary oxalate, or oxalate/creatinine ratio, as close to normal as possible [16]. The OHF best practices, developed from 2020 onwards by an international group of nephrologists, urologists, researchers, nurses, dietitians and geneticists, using the Delphi technique and a review of the literature published since 2010, complement the European consensus and are organised in three boxes of recommendations, on medical treatment (M1–M11), dialysis (D1–D3) and transplantation (T1–T7) [24].

Because this is an ultra-rare disease, the PNDS recommends that treatment be coordinated in a reference centre for rare kidney diseases or an affiliated competence centre, and that indications for RNA interference be discussed at the national multidisciplinary meeting of the ORKiD filière [16]. The paediatric or adult nephrologist coordinates a team with a urologist, radiologist, biochemist, dietitian, geneticist or genetic counsellor, psychologist, social worker, speech and language therapist for infants (prevention of oral feeding disorders), psychomotor therapist for children on intensive dialysis and school doctor [16]. The general practitioner is responsible for monitoring stone activity, initiating the response to urinary obstruction, monitoring kidney function, supporting adherence and preventing dehydration during gastroenteritis and pre-anaesthetic fasting [16].

7.2. Hyperhydration

Hyperhydration is the most important conservative measure. The European consensus recommends 3.5 to 4 L/day in adults and 2 to 3 L/m² of body surface area in children, spread over 24 hours, in all patients with suspected PH and preserved kidney function (statement 16, grades A–B) [20]. The PNDS adopts the same values, with the aim of a minimum urine output of 3 L/day in adults, and insists on abundant intake at bedtime; the PH1 GeneReviews recommends 2 to 3 L/m²/24 h at regular intervals day and night, and the PH2 and PH3 GeneReviews more than 2.5 L/m²/day [3, 5, 8, 16]. The European Association of Urology (EAU) proposes 1.5 L/m² in children for a urine output of at least 2.5 L/24 h, a value that the European consensus considers insufficient in PH [20]. In infants and young children, gastrostomy or a nasogastric tube is often necessary to maintain this intake, including overnight [8, 16, 20]. The OHF recommends the same 2 to 3 L/m²/day orally, gastrostomy when intake is difficult (infants, developmental delay) or the stone burden increases, with the additional advantage of facilitating nutrition and drug administration after transplantation, and intravenous fluids in the presence of vomiting, diarrhoea or reduced intake [24].

Hydration is monitored by urinary markers (statement 17) [20]. A urinary specific gravity below 1005 in the morning urine, measured by dipstick, corresponds to a urine output above 3 L/day; in France, dipsticks are no longer reimbursed [16]. Urine colour is the alternative [16]. In intercurrent illness with hypovolaemia (gastroenteritis, vomiting, fever), patients should seek care early for intravenous hydration [8]. Hyperhydration ceases to be applicable when residual urine output is lost on dialysis.

7.3. Crystallisation inhibitors and thiazides

Citrate binds urinary calcium and reduces the formation of calcium oxalate crystals; the aim is not to alkalinise the urine, because calcium oxalate crystallisation is independent of urinary pH [16, 20]. The evidence is limited: only a small cohort demonstrated benefit of citrate at a dose of 0.1–0.15 g/kg, and another study did not associate alkalinising agents with better kidney outcome in children with PH; the European consensus recommends it on the basis of the pathophysiological rationale (statement 18, grade C) [20]. Administration with meals improves gastrointestinal tolerance [16]. In France, potassium citrate is prescribed as an extemporaneous preparation (the PNDS gives the wording on the prescription that allows reimbursement), is available as a non-reimbursed supplement (Lithosolv®, 1 g per tablet), as Urocit-K® under a named-patient temporary authorisation from the French medicines agency, and in combinations of potassium and sodium citrates (Foncitril®, the least recommended form; Alcaphor®) [16]. The PH2 GeneReviews also mentions magnesium as a crystallisation inhibitor [3]. The guidelines consulted do not set a thiazide dose for PH; the dose shown in the table is that of the US hydrochlorothiazide label for oedema and hypertension, applied by extrapolation to hypercalciuria, an off-label use, and the PNDS restricts thiazides to situations of significant hypercalciuria and post-transplant recurrence [16, 61]. Doses above 50 mg/day in adults are associated with marked hypokalaemia [61]. Loop diuretics should be avoided, because they increase calciuria [8].

The OHF citrate dose, expressed in milliequivalents, overlaps with that of the European consensus in children: since each millimole of citrate corresponds to 3 mEq, the consensus 0.3–0.5 mmol/kg/day is equivalent to about 0.9–1.5 mEq/kg/day, within the range of 1–2 mEq/kg/day [20, 24]. In adults, the OHF 15–30 mEq/day lies below the PNDS starting dose of 4 g/day of potassium citrate (about 37–39 mEq, depending on whether the salt is monohydrate or anhydrous) [16, 24]. The main divergence concerns the objective: the OHF titrates citrate and magnesium to a urinary pH of 6.5–7.5, to urinary citrate (24-h or as a ratio to creatinine) and, if available, to the 24-h supersaturation profile, whereas the PNDS and the European consensus stress that the purpose of citrate is not to alkalinise the urine [16, 20, 24]. The OHF considers a pharmacological dose of citrate necessary, because increasing dietary citrate is of little effect in PH1, and indicates magnesium in the presence of low 24-h urinary magnesium, high supersaturation or increasing stone burden, without a dose of its own; the dose in the table is that of the oral maintenance regimen for primary hypomagnesaemia in Saudubray, applied by extrapolation [24, 60].

7.4. Diet

Oxalate restriction has little influence on the course of PH, because the excess is endogenous; the European consensus does not recommend a low-oxalate diet, owing to its impact on quality of life and the conflicting evidence, but suggests limiting foods with a very high content, such as spinach, rhubarb, chocolate and nuts (statement 19, grade D) [16, 20]. The PNDS recommends a normal-sodium diet (6 g of salt per day in adults; 50 to 75 mg/kg/day in children) to avoid the associated hypercalciuria, and a calcium intake of 800 mg to 1 g/day in adults, spread over the three meals to chelate dietary oxalate [16]. In children, calcium intake should be that recommended for age: 280 mg/day between 7 and 11 months, 450 mg/day between 1 and 3 years, 800 mg/day between 4 and 10 years and 1150 mg/day between 11 and 17 years, according to the European Food Safety Authority (2017) [16]. Oxalate precursors should be avoided: vitamin C (GeneReviews advises avoiding doses above the recommended daily allowance in PH1, above 1000 mg/day in PH2 and above 250 mg/day in PH3) and hydroxyproline, present in gelatines and gummies [3, 5, 8, 16]. A normal-protein diet is also recommended because of the associated CKD [16]. The OHF converges: the contribution of dietary oxalate to urinary oxalate is modest, so very oxalate-rich foods are limited without strict avoidance, the recommended daily calcium intake is maintained and high-dose vitamin C supplements are avoided [24].

7.5. Pyridoxine (vitamin B6)

Mechanism. Pyridoxal 5′-phosphate is the cofactor of AGT. At pharmacological doses, pyridoxine increases residual AGT activity in missense variants that compromise folding, cofactor binding or targeting, and acts as a chaperone; it has no effect on null variants or in PH2 and PH3 [8, 16]. Response is most likely in homozygotes for p.Gly170Arg, p.Phe152Ile and p.Ile244Thr, and possible with other non-truncating missense variants, such as p.Gly41Arg [8, 20].

Whom to test. The European consensus recommends testing the response to pyridoxine in all patients with PH1 and adjusting the dose according to urinary oxalate (statement 20, grade A), and starting it in all patients with suspected PH while awaiting the genotype; it should be stopped if genetic testing confirms PH2 or PH3 [20]. GeneReviews recommends the trial in all patients with one or two missense variants, including those with advanced CKD or kidney failure [8].

Dose. The sources differ regarding the maximum dose. The PNDS indicates starting at 5 mg/kg/day and titrating according to urinary oxalate (or plasma oxalate in stage 4 or higher) and tolerance [16]. The European consensus considers that the doses of up to 20 mg/kg recommended previously lack evidence, that a 2005 study showed no additional benefit above 5 mg/kg and that prolonged high doses are potentially neurotoxic; it suggests a maximum of 5 mg/kg/day and higher doses only in selected patients under monitoring [20]. GeneReviews proposes starting at 5 mg/kg/day with stepwise increases to a maximum of 10–20 mg/kg/day, measuring urinary oxalate at each step, and notes that most responders obtain maximum benefit with 5–8 mg/kg/day and little gain above 10 mg/kg/day [8, 62]. Saudubray indicates, for pyridoxine-responsive inborn errors of metabolism, including PH1, 50 to 500 mg/day orally, and notes peripheral neuropathy with doses above 900 mg/day in adults [60]. The reference dose is therefore that of the European consensus and the PNDS (5 mg/kg/day), higher doses being an individual option under monitoring. The sources consulted do not include a pyridoxine label with an approved indication for PH1; its use rests on the guidelines. The OHF proposes an oral trial with at least 5 mg/kg/day, generally not exceeding 10 mg/kg/day and with an absolute maximum of 1000 mg/day, in all patients with PH1 except carriers of variants known to be unresponsive, and recommends annual assessment of peripheral nerve function with doses above 10 mg/kg/day [24]. The OHF ceiling thus lies between that of the European consensus (5 mg/kg/day) and that of GeneReviews (10–20 mg/kg/day) [8, 20, 24].

Assessment of response. The classic criterion is a reduction of at least 30% in 24-h urinary oxalate, or its normalisation, after at least 3 months at the optimal dose [8, 20, 63]. The European consensus accepts assessment with at least two urinary oxalate measurements after at least 2 weeks of pyridoxine, defining response as a mean fall of more than 30%; in infants and young children the spot oxalate/creatinine ratio can be used, and with GFR below 30 mL/min/1.73 m² plasma oxalate is assessed [8, 20]. If the reduction does not reach 30%, pyridoxine is stopped; responders, about 30% of patients with PH1 according to the PNDS and 30 to 50% according to GeneReviews, continue it indefinitely, at the lowest effective dose, with at least two urinary oxalate measurements per dose step and six-monthly monitoring after stabilisation [8, 16, 20]. In the first prospective trial after 40 years of practice, pyridoxine reduced urinary oxalate in a subgroup of patients with PH1 [62]. The OHF repeats the 24-h urine at 3 months, defines response as a reduction of at least 30%, allows pyridoxine to be continued in the presence of a sustained fall of at least 15% without toxicity, which diverges from the discontinuation below 30% proposed by the other sources, and estimates that up to 20% of patients with PH1 normalise urinary oxalate and about 30% have a partial response; in patients with a single p.Gly170Arg allele, urinary oxalate falls by 25 to 50% [24]. In kidney failure the response is difficult to assess, and the OHF recommends continuing pyridoxine unless the variant is known to be unresponsive and starting it without waiting for confirmation in patients with suspected PH and rapidly progressive CKD [24].

Duration and transplantation. Pyridoxine is continued until any liver transplantation, at which point it may be stopped, and is maintained after isolated kidney transplantation in responders [8, 16]. In p.Gly170Arg homozygotes, recovery from dialysis dependence in three patients and a sustained response after isolated kidney transplantation have been described [64, 65].

Adverse effects. The safety profile is good even after decades of use [8]. Sensory peripheral neuropathy (paraesthesiae) has been described in patients without PH treated with very high doses (1–2 g/day in adults), and in one patient with PH1 the paraesthesiae resolved on discontinuation [8]. The PNDS mentions drowsiness and paraesthesiae as signs of intolerance [16]. In the presence of paraesthesiae, the dose is reduced or pyridoxine is stopped.

7.6. RNA interference therapies in PH1

7.6.1. Principle and classification

The two approved drugs are double-stranded small interfering RNAs (siRNAs) conjugated to N-acetylgalactosamine (GalNAc), which bind to the asialoglycoprotein receptor on hepatocytes and are taken up almost exclusively by the liver [21, 23]. In the hepatocyte, the siRNA promotes degradation of the target mRNA by RNA interference and reduces synthesis of the corresponding enzyme without altering the genome, so administration must be continued [21, 23]. This is a substrate reduction therapy (lumasiran) or a blockade of the terminal step of oxalate synthesis (nedosiran), and not a correction of the AGXT gene [20]. Lumasiran silences HAO1, which encodes glycolate oxidase, upstream of the AGT defect, and reduces available glyoxylate; nedosiran silences LDHA, the hepatic lactate dehydrogenase that converts glyoxylate to oxalate [21, 23]. The effect of lumasiran begins within the first two weeks and is maximal in the second month; that of nedosiran is observed at the first assessment, 30 days after the first dose [21, 23].

7.6.2. Lumasiran (Oxlumo®)

Presentation. Solution for subcutaneous injection of 189 mg/mL, in a single-dose vial containing 94.5 mg in 0.5 mL; maximum volume of 1.5 mL per injection site; administered by a healthcare professional into the abdomen, upper arms or thighs [21, 22].

Source: FDA label and European SmPC, with identical dosing [21, 22]. The dose is calculated from current body weight [21]. In patients on haemodialysis, the injection is given after the session; a missed dose is given as soon as possible and the schedule resumed from that date [21]. No adjustment is needed in renal impairment, including end-stage CKD and dialysis, although data are limited, or in mild hepatic impairment; in moderate or severe hepatic impairment, efficacy may be reduced and should be monitored [21, 22]. Concomitant pyridoxine does not alter the pharmacokinetics or pharmacodynamics of lumasiran [21, 22]. The guidelines do not propose doses different from those on the label.

Safety. The most frequent adverse reaction is injection site reaction (erythema, oedema, pain, haematoma, pruritus or discolouration), in about 35% of patients in the European SmPC and in 38% of those treated against 0% with placebo in ILLUMINATE-A according to the FDA label, generally mild and transient; abdominal pain was reported in 16% [21, 22]. The only contraindication in the European SmPC is severe hypersensitivity to the active substance or excipients; the FDA label has no contraindications [21, 22]. The European SmPC warns that lumasiran increases plasma glycolate, which may cause or worsen metabolic acidosis in patients with severe or end-stage CKD, who should be monitored for this effect [22]. Anti-drug antibodies were detected in 7 of 120 treated individuals (5.8%), with no identified clinical impact on safety, pharmacokinetics or pharmacodynamics [20–22]. No serious drug-related adverse events were identified in the trials [8].

7.6.3. Nedosiran (Rivfloza®)

Presentation. Solution for subcutaneous injection of 160 mg/mL, in a pre-filled syringe of 128 mg/0.8 mL or 160 mg/1 mL, which the patient aged 12 years or over or the caregiver can administer after training, and in an 80 mg/0.5 mL vial for supervised administration; injection into the abdomen, at least 5 cm from the umbilicus, or into the thigh [23].

Source: FDA label (revised March 2025) [8, 23]. A dose missed by more than 7 days is given as soon as possible and the monthly schedule resumed [23]. The label requires no adjustment with eGFR ≥30 mL/min/1.73 m² and in mild hepatic impairment; it has not been studied with eGFR below 30 or in moderate or severe hepatic impairment [23]. Injection site reaction occurred in 39% of patients on nedosiran and in none on placebo in PHYOX2; no treatment-emergent anti-drug antibodies were detected in 79 patients tested; there are no contraindications on the label [23].

7.6.4. Indications according to the European consensus

The 2023 ERKNet/OxalEurope consensus, reproduced in the PNDS, stratifies the indication for RNA interference into seven groups of patients with genetically confirmed PH1 (except group E) [16, 20].

ULN, upper limit of normal. Clinical deterioration is assessed individually, and episodes due to pre-existing stones are not a criterion of failure [20]. In patients who receive a kidney transplant during treatment, the response is assessed by plasma oxalate, taking into account eGFR and stored oxalate, because high urinary oxalate after transplantation may reflect release from bone; the consensus allows consideration of stopping lumasiran 3 months after kidney transplantation if urinary oxalate normalises, measuring urinary oxalate monthly and restarting if it exceeds the ULN [20]. Continuation of any new therapy should be based on an annual reassessment of biochemical and clinical efficacy (statement 48), and the benefit should be weighed against long-term risks that are still unknown (statement 41) [20]. In the absence of access to RNA interference, the consensus suggests trying investigational drugs, such as stiripentol (statement 46, grade D) [20].

The PNDS adds that lumasiran reduces urinary oxalate by about 60%, that its medium-term tolerability is excellent, that long-term data on clinical outcomes (urolithiasis, kidney function, oxalosis) and quality of life are lacking, and that, as a very high-cost medicine, indications should be discussed at the national meeting of the ORKiD filière or with a specialist [16]. The Haute Autorité de Santé (HAS) rated it as having important medical benefit and a level III improvement in medical benefit [16]. The PNDS does not include nedosiran as a treatment available in France and states that, at the time, the results in PH2 were disappointing [16].

The OHF best practices formulate the indication more simply: after genetic confirmation of PH1, start RNA interference, if available, in all patients who are not fully pyridoxine-sensitive; continue if there is efficacy, defined as normal or near-normal urinary oxalate or a reduction of more than 30% from baseline, and, in advanced CKD or on dialysis, in the presence of a documented reduction in plasma oxalate [24]. The choice between lumasiran and nedosiran depends on experience and access, because there is no head-to-head comparison and the separate trials showed similar effects on urinary oxalate, and dosing follows each drug's label [24]. With preserved kidney function and access to RNA interference, the OHF does not recommend liver transplantation [24]. Compared with the European consensus, the OHF does not stratify patients into groups or set stopping criteria at month 6, and in advanced CKD accepts any documented reduction in plasma oxalate, whereas the European consensus considers a reduction of less than 20% a failure [20, 24].

7.6.5. Monitoring on RNA interference

There is a minor divergence between the two sources: the PNDS makes fundoscopy, echocardiography and bone imaging dependent on symptoms in CKD 1–3, whereas the European consensus includes them in the periodic assessment [16, 20]. The OHF proposes measuring plasma and urinary oxalate every 3 to 6 months on pyridoxine or RNA interference, to confirm adherence and maintenance of efficacy [24].

7.6.6. Real-world results and special situations

In the French DAILY-LUMA cohort, which included 76 patients (54 children) with a median age of 13 years (4–33) at the start of lumasiran, 24 of them on dialysis, 73% met at 3 months the composite criterion of normalisation or a reduction of more than 30% in the urinary oxalate/creatinine ratio (eGFR above 30) or in plasma oxalate (eGFR below 30) [66]. There was no significant association between genotype and response, although with a trend towards lower response in B6-sensitive forms; age at diagnosis and at start of treatment were the only determinants, with better response in the paediatric age group, and the authors suggest continuing or starting pyridoxine in sensitive forms even on lumasiran [66]. A German series described variable response in children, and complete normalisation is not achieved in all patients [8, 67]. In the French national cohort of 2015–2019, 58% of patients with PH1 were receiving RNA interference [44]. The Netherlands evaluated a controlled access model for lumasiran as a route of access to orphan medicines [68]. Concomitant treatment with lumasiran and nedosiran in a child has been published, a strategy not evaluated in trials [69].

After isolated kidney transplantation, the use of siRNA is documented only in reports and small series: an adult had acute rejection with signs of oxalate nephropathy and recovered with anti-rejection treatment, a 5-year-old child with late diagnosis kept the graft with intensive dialysis and lumasiran, a series of five patients had no oxalate nephropathy of the graft, and in 2026 another successful isolated kidney transplant on lumasiran was described [20, 70, 71]. A geriatric patient with PH1 diagnosed on dialysis and treated with lumasiran has also been described [72].

7.6.7. Regulatory status

Sources: [21–23, 31, 32, 75]. The absence of registration in the databases consulted does not demonstrate that there is no access by other routes (early access programmes, importation or exceptional authorisations). In France, lumasiran obtained authorisation in November 2020 and PH is recognised as an inherited metabolic disease on the list of long-term conditions (ALD 30, no. 17), with exemption from patient co-payment [16]. In Italy, the medicines agency approved lumasiran for any age (resolution 237/2022) [56].

7.6.8. Clinical trials

Limits of the evidence. The trials are small (15 to 39 patients in the main studies), only two are placebo-controlled with a 6-month controlled period, and the primary endpoint is always biochemical (urinary or plasma oxalate), a surrogate marker accepted in this disease because it correlates with the risk of kidney failure [34, 38, 76, 86]. Data on stone events, nephrocalcinosis and eGFR come from open-label extensions without a comparator group, in which all patients receive the drug, and do not yet demonstrate prevention of kidney failure or oxalosis [20, 77, 83]. The populations, inclusion criteria and outcome definitions differ between the lumasiran and nedosiran programmes (for example, mean urinary oxalate over months 3–6 versus area under the curve over days 90–180), so the percentage reductions cannot be compared directly between drugs. The PHYOX2 results vary according to the source: the publication reports normalisation or near-normalisation in 64.7% of patients with PH1, the European consensus 81% and a reduction of 59%, and the FDA label a 56% difference in the change in urinary oxalate, reflecting different analyses and definitions [20, 23, 34]. In PH2 and PH3, results with nedosiran were negative or inconclusive (no consistent effect in the 6 patients with PH2 in PHYOX2 and primary endpoint not met in PHYOX4) [34, 35]. Experience with advanced CKD, dialysis and isolated kidney transplantation is limited, for lumasiran, to the 21 patients in ILLUMINATE-C and to case reports, and does not yet exist for nedosiran outside ongoing trials [8, 81].

7.7. Dialysis

No dialysis modality compensates for endogenous oxalate production; dialysis is a temporary treatment, as short as possible, while awaiting transplantation, or an adjunct when the graft has delayed function [8, 16]. Endogenous production in PH1 is estimated at 4 to 7 mmol/day (28–37.7 mmol/week), whereas usual dialysis regimens remove 1.0 to 1.4 mmol/day [20]. Weekly removal is similar with conventional thrice-weekly haemodialysis and daily peritoneal dialysis (3.9 and 3.5 mmol/1.73 m², respectively), but clearance per minute is much higher with haemodialysis (116 versus 7 mL/min/1.73 m²); six weekly sessions of 4.5 h with a high-flux filter removed 24 mmol/1.73 m² per week [3, 20].

The European consensus suggests considering kidney replacement therapy before kidney failure in patients with PH1 at high risk of oxalosis due to raised plasma oxalate or with comorbidities (statement 21); in the absence of access to, or response to, oxalate-lowering therapies, it recommends intensified haemodialysis, titrated to the clinical picture and plasma oxalate, with a high-flux dialyser (capillary surface area >1 m² per m² of body surface area) and maximal blood flow (>150–200 mL/min/m²) (statements 22 and 23) [20]. To intensify, it is preferable to increase the weekly number of sessions rather than lengthen each session, because efficiency falls over the session as plasma oxalate declines [20]. The PNDS recommends starting dialysis somewhat earlier than in other CKD stage 5, weighing plasma oxalate, signs of oxalosis and social factors, with 5 to 6 short weekly sessions (2–3 h), high flux and maximal flow, acknowledging that even so extraction remains below 50% of production [16]. Combining daytime haemodialysis with nocturnal peritoneal dialysis is possible in infants, at the cost of a very heavy burden for the child and family and a higher risk of infection [16, 20]. Intensive dialysis causes hypophosphataemia, which worsens bone disease and must be corrected [16, 20]. Patients should be dialysed in a centre familiar with the disease or with its support, to adjust intensity to the end-of-dialysis oxalate [16].

Pre-dialysis plasma oxalate targets differ between sources: GeneReviews advises keeping oxalate below 30–45 µmol/L, the supersaturation threshold, as much as possible between sessions; the PNDS advises below 50–60 µmol/L; and the European consensus suggests 50–70 µmol/L, the concentration observed in dialysed patients without PH, taking into account inter-laboratory differences and residual diuresis (statement 24) [8, 16, 20]. In PH2, plasma oxalate rises when renal clearance falls below 40 mL/min/1.73 m², and GeneReviews favoured early dialysis or pre-emptive kidney transplantation [3]. In PH3, plasma oxalate above 35–50 µmol/L justifies dialysis or transplantation [5].

The OHF best practices detail dialysis in PH without effective oxalate-lowering therapy [24]. Initiation is indicated with plasma oxalate above 30–45 µmol/L or eGFR below 30 mL/min/1.73 m² in PH1 (below 20 in PH2 and PH3), bearing in mind that oxalate for a given GFR varies with hepatic production, type, genotype and treatment; if plasma oxalate is unknown in a patient with known or suspected PH in CKD 4–5, particularly if oligoanuric, dialysis begins while the result is awaited, the sample preferably being taken before the first session [24]. In infants with PH1, whose GFR is physiologically low and rises in the first months, creatinine and plasma oxalate are measured every 2 weeks, and dialysis is started if creatinine is higher than expected for age and oxalate rises progressively above 30–45 µmol/L [24]. Most of the clearance occurs in the first 1–2 h of each session, with marked rebound afterwards; frequent sessions are therefore more effective than long, widely spaced sessions, and thrice-weekly haemodialysis or peritoneal dialysis alone are insufficient without significant residual kidney function [24].

The OHF plasma oxalate targets coincide with those of GeneReviews and are more demanding than those of the PNDS and the European consensus, and the OHF 6–7 weekly sessions exceed the 5–6 sessions of the PNDS [8, 16, 20, 24].

7.8. Transplantation

7.8.1. PH1

Until 2020, total liver transplantation was the only intervention that restored AGT activity, and it remains the only cure for PH1 [8, 20]. The native liver should always be removed (statement 25, grade A); auxiliary liver transplantation is considered obsolete, because it does not sufficiently reduce oxalate production [8, 20]. Combined liver-kidney transplantation, simultaneous or sequential (liver then kidney), has better kidney graft survival than isolated kidney transplantation (87% versus 14% at 15 years; adjusted hazard ratio for graft failure 0.14; 95% CI 0.05–0.41), with similar patient survival; other studies report 5-year kidney graft survival of 48–89% with combined transplantation and 14–45% with isolated kidney [20]. In the OxalEurope registry of 267 transplanted patients, event-free survival was better after combined transplantation than after isolated kidney in pyridoxine-insensitive patients (p<0.001), but not in sensitive patients (p=0.411); results were comparable between simultaneous (n=159) and sequential (n=37) transplantation, and pre-emptive liver transplantation in 12 patients had poor results, so it is not recommended [8, 20, 87]. In the French cohort of Harambat et al., 83% of the 40 isolated kidneys were lost to recurrence, with a median graft survival of 11 months, whereas 65% of the 52 combined transplants had functioning grafts after a median of 5 years; in the Netherlands, all 17 isolated kidneys were lost to recurrence (median survival 2.7 years); in Australia and New Zealand (1965–2015), graft loss was 47% in the 19 transplants in patients with hyperoxaluria, against 28% in reflux nephropathy [16, 42, 45, 88].

The recommendations of the European consensus are: combined liver-kidney transplantation in patients with advanced PH1 (eGFR <30) who do not respond to pyridoxine and have no access to RNA interference (statement 27); choice between a simultaneous and a sequential strategy according to the clinical situation and the preference of the surgical team (statement 26); and isolated kidney transplantation in patients in CKD 5D homozygous for pyridoxine-responsive variants (statement 29) [20]. With RNA interference, isolated kidney transplantation, from a deceased or living donor, becomes theoretically possible, with the drug continued for life; the PNDS stresses that, at the time of writing, only one favourable observation had been published and that massive mobilisation of tissue oxalate after transplantation may cause recurrence in the graft despite precautions [16, 89]. The European consensus recommends that the decision not to perform liver transplantation in a patient in CKD 5 on lumasiran be taken case by case, with extensive monitoring, because lumasiran does not act on oxalate already stored [20]. GeneReviews adds that RNA interference is expensive and not universally available, that kidney transplantation remains an option for those who reached kidney failure before diagnosis or without access to the drug, and that the suitability of a heterozygous parent or sibling as a living liver donor is uncertain [8].

The OHF best practices propose referral for transplant assessment at CKD 3b or 4, before plasma oxalate exceeds 30–45 µmol/L, and planning transplantation when eGFR falls below 45 mL/min/1.73 m² in the absence of effective lowering therapy [24]. The type of transplant depends on the type of PH, the lowering therapy available, its efficacy and the guarantee of access after transplantation: with complete response to pyridoxine or control of production by RNA interference, isolated kidney transplantation is considered, already described successfully in p.Gly170Arg homozygotes on pyridoxine; in pyridoxine responders who do not normalise urinary oxalate or with extensive oxalosis, liver-kidney transplantation or isolated kidney on RNA interference; without complete response to pyridoxine or access to RNA interference, combined or sequential liver-kidney transplantation, with kidney graft survival up to six times higher than that of isolated kidney at 5 and 15 years [24]. Before an isolated kidney on RNA interference, in a pyridoxine-sensitive patient or with PH2, and before combined transplantation, plasma oxalate should ideally be below 60 µmol/L [24]. With severe oxalosis and plasma oxalate above 70 µmol/L, the OHF recommends postponing transplantation, with intensive dialysis and lowering therapy; below that value, the benefit of transplantation outweighs that of further months of dialysis, even if the target of 30–45 µmol/L is unattainable [24]. Nephrectomy of the native kidneys, before or during transplantation, may be considered to protect the graft from stored and excreted oxalate, but rests on three case reports and is decided individually [24]. The transplant centre should have rapid plasma oxalate results, haemodialysis or continuous kidney replacement therapy available immediately and pathologists able to identify oxalate crystals in biopsies, and should minimise donor factors that favour delayed graft function (age, size, cold ischaemia prolonged by distance) [24].

The OHF position on isolated kidney transplantation on RNA interference is more favourable than that of the European consensus, which requires a case-by-case decision and extensive monitoring, and than that of the PNDS, which at the time had a single published observation; all three sources recognise that experience is limited [16, 20, 24].

In the immediate post-transplant period, mobilisation of stored oxalate is high, with a risk of acute oxalate nephropathy and early graft loss [16]. Teams apply conservative treatment strictly (hyperhydration, citrate, pyridoxine in responders and intensive haemodialysis if plasma oxalate is very high) and reduce these measures progressively according to plasma oxalate; urinary oxalate may remain raised for months or years, and clearance of deposits takes months to more than five years after liver transplantation or RNA interference [8, 16]. After liver transplantation, urinary and plasma oxalate should be measured at least six-monthly until normal on at least three occasions (statement 30); after kidney transplantation on pyridoxine or RNA interference, at least six-monthly until normal and then annually (statement 31) [20]. Crystalluria is monitored several times a week in the immediate post-transplant period, with the aim of negative crystalluria or an oxalate crystal volume below 100 µm³/mm³ [16, 20].

7.8.2. PH2

In PH2, GR/HPR has broad tissue expression, and liver transplantation does not correct the whole deficiency [3, 16]. The PNDS considers isolated kidney transplantation the usual treatment for kidney failure, with a small but real proportion of graft losses due to recurrence [16]. The European consensus suggests considering liver transplantation in advanced PH2 (eGFR <30; statement 28, grade C), on the basis of the poor results of isolated kidney in the OxalEurope registry: in 10 of the 22 patients who reached CKD 5, cumulative kidney graft survival was 43% at 1 year and 29% at 5 years [17, 20]. Data on combined transplantation are scarce: two successful cases with normalisation of urinary oxalate and glyceric aciduria, one of them after failure of a previous isolated kidney, one combined transplant with primary non-function of the liver and death from sepsis, and one liver transplant after kidney that neither reduced urinary oxalate nor prevented graft loss [3, 20]. The OHF considers that some patients with PH2 do well with isolated kidney and reserves liver transplantation for significant oxalosis, as an individual decision [24].

7.8.3. PH3

Severe kidney failure is exceptional in PH3, and there is no transplant experience allowing specific recommendations [5, 16]. In the absence of reports of transplantation in PH3, the OHF recommends isolated kidney transplantation until more evidence is available [24].

7.9. Urological treatment

The European consensus recommends following the EAU algorithms (statement 32) and suggests percutaneous nephrolithotomy and ureteroscopy rather than extracorporeal shock wave lithotripsy (ESWL) (statement 33, grade C) [20]. In a paediatric cohort, ESWL had a stone-free rate of 20% (1/5) in PH1 and 47% (8/17) in PH2; in a series of 54 procedures in 14 patients with PH1, primary ureteroscopy achieved 57% stone-free and percutaneous nephrolithotomy 70%, rising to 90% after a second procedure [20]. Whewellite stones are among the hardest (density of 1200–1700 Hounsfield units on CT, although density does not reliably identify composition), incomplete fragmentation leaves fragments that grow quickly, and lower-pole or parenchymal stones respond less well [8, 16]. GeneReviews prefers ureteroscopy because it causes less kidney injury [8].

The PNDS retains ESWL as a first-line option in selected cases, because it is minimally invasive. In children, it proposes ESWL under general anaesthesia for pyelocalyceal stones smaller than 10 mm, ureteroscopy for those of 10–20 mm or after ESWL failure, percutaneous nephrolithotomy or ureteroscopy for multiple stones, ureteroscopy for stones of the lumbar ureter above the iliac vessels and of the pelvic ureter, cystoscopy for bladder stones and minimally invasive surgery for bladder stones above 20 mm, always with sterile urine culture and intravenous hyperhydration after the procedure [16]. In adults, it limits ESWL to renal stones smaller than 2 cm and ureteral stones smaller than 1 cm, considers the lower calyx a poor indication, recommends endoscopy after two failed sessions and indicates flexible ureteroscopy for renal stones of 5 to 20 mm, percutaneous nephrolithotomy (conventional or miniaturised) above 20 mm and treatment in a specialised centre above 20 mm [16]. The divergence between the European consensus and the PNDS is therefore one of degree: both recognise the lower efficacy of ESWL for these stones, but the consensus advises against it as the preferred approach. Contraindications to ESWL include anticoagulation that has not been stopped, pregnancy and certain skeletal diseases, and urine should be strained after the procedure for fragment analysis [16].

Procedures should be indicated sparingly, because they may trigger acute crystal nephropathy [8, 16]. Hyperhydration should be maintained throughout the perioperative period, avoiding any preoperative fluid fasting, with monitoring of hydration status, in collaboration with the anaesthetist [16, 20]. In obstructive emergencies, the priority is urinary diversion [16]. Imaging follow-up should be lifelong (statement 35): after two years of six-monthly imaging, at least annually, without discharge from the clinic [20]. In adults, the PNDS recommends a CT urography at least once in a lifetime, if kidney function permits, to study the excretory tract before a procedure [16].

7.10. Infantile oxalosis and paediatric specificities

Infants with infantile oxalosis should be treated in paediatric nephrology centres with experience of dialysis and solid organ transplantation in young children, because of the difficulty of vascular access, tube-feeding nutritional prescriptions, frequent fractures and the electrolyte disturbances of intensified dialysis [20]. Bone radiographs are performed only in the presence of bone symptoms (statement 38), and eye examination and echocardiography at diagnosis (statements 39 and 40) [20]. Lumasiran was effective in the infants and young children of ILLUMINATE-B and was used from the first hours of life in the case in section 10 [56, 79]. The PNDS highlights gastrostomy, the hypophosphataemia of daily haemodialysis and the question of preventing infantile oxalosis with early RNA interference in screened families [16]. At school, the individualised care plan should guarantee free access to water and toilets and adaptation of meals [16].

7.11. Pregnancy and lactation

Pregnancy does not appear to be an important risk factor for kidney failure in most patients with PH, but there are cases with persistent deterioration and one patient with decline of the kidney graft after deliveries; successful pregnancies have been described after isolated kidney transplantation and after liver-kidney transplantation [8, 90]. Outcomes in PH3 are similar to those in PH1 and PH2, and women with good kidney function had good outcomes [5]. Pregnancy requires joint monitoring by the obstetrician and the nephrologist, of kidney function and urolithiasis, during pregnancy and the post-partum period [3, 8]. Hydration may be difficult in the first trimester or with hyperemesis, and intravenous fluids are then needed; urinary tract infections should be treated promptly; pyridoxine is continued in responders [5, 8].

RNA interference agents have not been studied in human pregnancy. For lumasiran, studies in rats and rabbits showed no effects at exposures of 45 and 90 times the maximum human dose, and the European SmPC allows use in pregnancy to be considered, weighing the expected benefit for the woman against the risk to the fetus [21, 22]. For nedosiran, mice showed no effects, but in rabbits, in which the drug is not pharmacologically active, there was fetal loss with maternal toxicity at exposures equivalent to the maximum human dose and cardiovascular and skeletal malformations at about twice that dose; in PHYOX3, one patient discontinued because of pregnancy [23, 83]. The GeneReviews authors advise stopping RNA interference agents before conception and during pregnancy, which is more restrictive than the European SmPC for lumasiran [8, 22]. There are no data on transfer into breast milk; the decision to breastfeed weighs the benefit of breastfeeding against that of treatment [8, 22, 23].

7.12. Agents and situations to avoid

7.13. Therapeutic education, adherence and transition

The main difficulty of treatment is long-term adherence to hyperdiuresis, which is very demanding; poor adherence rapidly leads to irreversible kidney destruction [16]. The PNDS recommends teaching the patient to monitor urine colour and volume and urinary specific gravity, to maintain a normal-sodium and normal-protein diet, addressing stress and pain management, acceptance of the disease and professional integration, and carefully preparing the transition from paediatric to adult medicine [16]. In France there is no therapeutic education programme dedicated to PH; patients join CKD or transplant programmes, including paediatric ones [16]. Social support includes recognition of disability and parental leave to care for sick children [16].

7.14. Investigational therapies

None of the approaches in this section is authorised for PH. The level of evidence for each is indicated in the table and the text, distinguishing preclinical studies, human trials, sponsor press releases and congress abstracts.

The European consensus identifies as priority research questions the long-term safety and efficacy of RNA interference agents, their effect on systemic oxalosis and on the need for liver transplantation in patients in CKD stage 5, the treatment of PH2, the pathophysiology and course of PH3, the vitamin B6 response of variants other than p.Gly170Arg and p.Phe152Ile, the nature of intrafamilial phenotypic discordance in PH1, the development of a reliable diagnostic test in patients presenting in kidney failure and early assessment of systemic oxalosis [20]. The PNDS adds prevention of infantile oxalosis by early treatment in screened families [16].

Ongoing observational studies include BONAPH1DE (NCT04982393, 207 participants), the Rare Kidney Stone Consortium registry, the OxalEurope registry, an Italian paediatric cohort of patients treated with lumasiran (NCT07874074) and the Lyon cohort (NCT06225882) [51].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All three primary hyperoxalurias have autosomal recessive inheritance [3, 5, 8, 16]. The sources consulted do not describe dominant forms of any of them.

Heterozygotes are asymptomatic. In PH1 they may have reduced hepatic AGT activity, but have normal urinary oxalate and do not develop urolithiasis or kidney disease attributable to carrier status [8]. In PH3, some heterozygotes have raised urinary oxalate precursors, without hyperoxaluria or a urolithiasis rate higher than that of the general population [5].

Where only one parent is a carrier, after confirmation of biological parentage, consideration should be given to a de novo variant in the proband, germline or post-zygotic mosaicism in one of the parents, an undetected deletion on the other allele or uniparental isodisomy of the chromosome carrying the variant, a mechanism documented in one case of PH1 [8].

8.2. Cascade testing and carrier testing

Confirmation of the proband's genotype is what makes it possible to offer genetic counselling and carrier testing to relatives in at-risk families; the PNDS stresses that the genotype is the only means of definitive diagnosis, because metabolite measurements may fail, particularly in asymptomatic individuals [16]. Counselling is provided at a dedicated appointment, by a geneticist or genetic counsellor [16, 20].

Genetic testing of siblings is recommended at any age, even if asymptomatic, as soon as the diagnosis is established in one of them [5, 8, 16, 50]. The justification is threefold: intrafamilial variability prevents prediction of the phenotype from that of the affected sibling, asymptomatic biallelic patients are at increased risk of urolithiasis and kidney injury and need the same management, and effective treatments exist [8, 50]. Molecular testing is more reliable than urinary oxalate, which is variable in childhood; when the familial variants are not known, biochemical assessment remains [3]. The PH2 GeneReviews recommends storing DNA when the molecular diagnosis has not been confirmed [3]. Carrier testing in relatives requires prior knowledge of the family's variants [8].

Testing the partner of a patient is relevant mainly when the partner belongs to the same population with founder variants, for example in PH3 in individuals of Ashkenazi Jewish origin, in whom the carrier frequency is about 1 in 55 [5]. The European consensus recommends genetic counselling for couples in which both members carry variants predisposing to PH1, to allow early diagnosis and treatment of an affected child [20].

8.3. Prenatal and preimplantation diagnosis

Once the pathogenic variants in the family have been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are technically possible for all three types [3, 5, 8]. In France, these options are accepted in families at risk of PH1, after discussion at a multidisciplinary prenatal diagnosis centre [16]. The historical approaches, measurement of AGT activity in fetal liver biopsy and measurement of metabolites in amniotic fluid, have been replaced by DNA analysis [1].

The reproductive decision has particular features in this disease. The severity of PH1, the possibility of infantile oxalosis, the demands of conservative treatment, the complications of transplantation and the shortage of organs may weigh on the decision of parents who already have an affected child [8]. Conversely, prenatal diagnosis allows treatment to start from birth, with a clinical trajectory different from that of the sibling not treated early, as illustrated by the case in section 10 [56].

8.4. Donor selection and counselling of minors

In candidates for living kidney or liver donation to a patient, molecular testing makes it possible to exclude an affected relative [8]. The suitability of a heterozygous parent or sibling as a liver donor is uncertain, because it has not been established whether the carrier's reduced enzyme activity is sufficient [8]. For kidney donation, the OHF considers that donor heterozygosity does not preclude donation of an isolated kidney, and good results with obligate heterozygous donors have been described [24]. Screening of at-risk relatives is also relevant before donation, so as not to transplant a kidney from an individual with unrecognised PH [8].

Testing of asymptomatic minor siblings is, in this disease, a justified exception to the general rule of deferring predictive testing until adulthood, because treatment and monitoring exist that alter the prognosis in childhood [5, 8, 16, 50]. The diagnosis should be disclosed at a dedicated appointment, with appropriate time and setting, in the presence of a companion chosen by the adult patient or of both parents and the child, by a doctor with experience of the disease, progressively addressing the mode of transmission, the mechanisms, medical and surgical treatment and possible complications [16].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and incidence

Clinical and genomic estimates diverge systematically, and each study measures a different quantity: clinical estimates count diagnosed patients, whereas genomic estimates calculate the expected frequency of biallelic genotypes from allele frequencies in population databases.

Comparison of these figures points to probable underdiagnosis. The genomic prevalence of PH3 is similar to that of PH1 and about twice that of PH2, but PH3 accounts for only 7 to 20% of diagnosed patients, which indicates underdiagnosis, incomplete penetrance or both [5, 8, 33]. In clinical registries, the distribution is about 70 to 80% PH1, 10% PH2 and 7 to 20% PH3, with about 10% of patients without an identified genetic cause [5, 16, 33]. The PNDS adds that prevalence is higher the greater the consanguinity in the country considered and that the frequency of PH2 and PH3 is poorly known and probably underestimated [16].

9.2. Burden in end-stage kidney disease

PH accounts for about 1% of cases of end-stage kidney disease in children in France and represents 1 to 2% of children on kidney replacement therapy in Western Europe and North America, but 10 to 17% in the Middle East [8, 16]. The PH2 GeneReviews indicates that PH accounts for 0.7 to 1.6% of paediatric end-stage kidney disease [3]. In resource-limited countries, the commonest presentation of PH1 is CKD stage 5, especially below the age of 5, and 16 to 65% of patients already present in kidney failure [20].

9.3. Founder populations and consanguinity

The sources consulted contain no data on prevalence, incidence or variant distribution from Portugal or Brazil. The absence of these data in the main sources of this article does not demonstrate that no national publications on the subject exist.

9.4. Diagnostic delay and inequalities of access

Diagnostic delay is a persistent and quantified problem. In the French national cohort of diagnoses between 2015 and 2019, the median delay was 1.2 years in children and 30 years in adults, and 23% of patients were on dialysis at diagnosis [44]. About 10% of patients in several cohorts are diagnosed only by recurrence in the kidney graft [8, 42]. GeneReviews attributes underdiagnosis to clinical variability, lack of awareness of the disease and the lack of laboratories able to measure oxalate and perform genetic testing, particularly in developing countries [8].

The European consensus devotes a section to resource-limited countries and recommends promoting clinical suspicion, screening patients on dialysis or in CKD stage 5 of unknown cause, using ultrasound and radiography, which are accessible and informative about stone burden, nephrocalcinosis and bone disease, measuring 24-h urinary oxalate and calcium correctly and repeating them, measuring plasma oxalate in patients in CKD stage 4 or higher with nephrocalcinosis, and establishing collaborations with institutions in higher-resource countries for genetic diagnosis [20]. It also stresses that early, low-cost conservative treatment (hydration, including by gastrostomy in infants, crystallisation inhibitors and pyridoxine) is fundamental, particularly in hot climates, and that the lack of intensive dialysis and liver transplantation in these countries makes access to RNA interference agents more important, which would require differential pricing [20]. There are no epidemiological data on PH2 and PH3 in these countries [20].

Access is also unequal in Europe. The Netherlands created a controlled access route for lumasiran for orphan medicines [68]. In France, indications are discussed at a national meeting because of cost, and the disease is included on the list of long-term conditions (ALD 30, no. 17), with exemption from patient co-payment [16]. In Portugal, the lumasiran presentation appears in Infomed as not marketed, with European authorisation and as a medicine subject to restricted medical prescription [75]. In Brazil, consultation of the regulatory authority's open data did not identify registration of lumasiran or nedosiran [73].

9.5. Special populations

In infants and young children, the physiologically low GFR in the face of high oxalate production contributes to the severity of the infantile form, and treatment requires centres with experience of dialysis and transplantation at this age [8, 20]. In patients on long-term dialysis, oxalosis is progressive and determines morbidity and mortality [8]. In adolescents, adherence to hyperdiuresis is the main problem, and the transition to adult medicine should be prepared [16]. In older adults, the diagnosis may be made very late, including on dialysis [72]. Patients with advanced CKD accumulate the comorbidities of kidney failure with those of oxalosis, including refractory anaemia, bone disease, hypothyroidism and hypogonadism [8, 16].

9.6. Reference networks and patient associations

In France there is also a freely accessible series of podcast episodes devoted to primary hyperoxaluria, aimed at patients and families [16].

10. Illustrative Clinical Case

The case described by Peruzzi et al. in Turin illustrates the effect of prenatal diagnosis and treatment from the first hours of life in a family with two affected siblings and different trajectories [56].

Family history. The older brother, born before lumasiran was available, reached kidney failure in the second month of life, underwent intensive haemodialysis and combined liver-kidney transplantation at 13 months, lost the kidney graft one month later due to recurrence of oxalate nephropathy resulting from mobilisation of deposits, received a second kidney transplant and developed post-transplant lymphoproliferative disorder [56]. The parents are first cousins and heterozygous [56].

Prenatal diagnosis. In the next pregnancy, chorionic villus sampling at 11 weeks identified in the fetus the AGXT variant NM_000030.3:c.731T>C, p.(Ile244Thr) in the homozygous state, considered partially pyridoxine-responsive [9, 56]. The pregnancy was monitored; maternal oxalate and glycolate remained normal; there was gestational diabetes and the fetus was large for gestational age. Delivery was by caesarean section at 37 weeks, with a weight of 4120 g and an Apgar score of 9/9 [56].

Findings at birth. In cord blood, oxalate was 15 µmol/L (normal <10). In amniotic fluid, oxalate was 55 µmol/L (reference range 19–71) and glycolate 2 µmol/L (66–109). In the first urine, the oxalate/creatinine ratio was 401 µmol/mmol (<360). At 6 hours of life, plasma oxalate was 32 µmol/L, the oxalate/creatinine ratio 573 µmol/mmol, the glycolate/creatinine ratio 15 and plasma glycolate 107 µmol/L [56].

Management. At 6 hours of life, subcutaneous lumasiran 6 mg/kg and pyridoxine 10 mg/kg/day were started, with intravenous hydration of 240 mL/kg/day for 16 days, then oral water, potassium citrate 500 mg in 500 mL/day and breastfeeding. Lumasiran was repeated at a dose of 6 mg/kg at 30 and 60 days, followed by 3 mg/kg monthly and, after the infant reached 10 kg, 6 mg/kg every 90 days [56].

Course. Plasma oxalate rose to a peak of 108 µmol/L on day 6, above the supersaturation threshold of about 50 µmol/L, with a creatinine of 0.3 mg/dL; it fell to 65, 56 and 62 µmol/L on days 10, 20 and 30, to 31 and 17 µmol/L on days 45 and 60, to 12 µmol/L at 80 days (after three doses) and to 6 µmol/L from the fourth dose onwards. The urinary oxalate/creatinine ratio peaked at 4173 µmol/mmol at 13 days, fell to 765 at 80 days and to 335 after four doses, normalising thereafter. 24-h urinary oxalate was 360 and 400 µmol/day on days 2 and 6. Plasma glycolate rose to 1732 µmol/L, about 200 times the normal value, without acidosis. Renal ultrasound was normal at birth and showed only minimal hyperechoic spots in the first two months; at 24 months there were no deposits, creatinine was 0.2 mg/dL, growth was normal and there were no adverse effects [56].

Critical reading. This management is not established practice. The authors point out three limitations: the latency of at least 15 days before lumasiran takes effect, more than three months until normalisation of the markers and the fact that they did not wait for assessment of the response to pyridoxine, which would be the recommended sequence for a partially responsive variant; they therefore consider such early use debatable [56]. The guidelines do not recommend starting RNA interference in an asymptomatic newborn: group F of the European consensus, of patients without ongoing clinical disease, requires established pyridoxine resistance and urinary oxalate above 1.5 times the reference limit, and the question of preventing infantile oxalosis by early treatment in screened families is framed by the PNDS as an open question [16, 20]. The marked rise in plasma glycolate, an expected consequence of the mechanism of lumasiran, was well tolerated in this infant with normal kidney function, but the European SmPC warns of the risk of metabolic acidosis in patients with severe or end-stage kidney failure [22]. Figure 1 of the original article shows the course of oxalate and glycolate in blood and urine; the legend was read in the full text, but the figure itself was not consulted, because the image page in the repository was not accessible [56]. Editorial assistance for the article was funded by the marketing authorisation holder for lumasiran, and conflicts of interest are declared in the publication [56].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Kidney failure occurs in more than 70% of patients with PH without targeted therapy [20]. Prognosis depends on type, genotype, age at presentation and the presence of nephrocalcinosis.

The factors of worse prognosis in PH1 are homozygous null or nonsense variants, nephrocalcinosis (3.17-fold higher risk of kidney failure), higher urinary oxalate, infantile presentation and late diagnosis, particularly after kidney transplantation [16, 38, 41, 42]. The favourable factors are homozygous pyridoxine-responsive variants, early diagnosis, including by family screening, and timely conservative treatment [8, 38, 50]. Intrafamilial variability prevents individual prediction from genotype [8, 16].

On RNA interference, the longest follow-up data show sustained reduction in urinary oxalate and stable eGFR: the final ILLUMINATE-A analysis at 60 months showed stable eGFR, with stone events of 0.47 and 0.54 per patient-year and improvement in the grade of medullary nephrocalcinosis in 21 of 28 patients (75%); the phase 2 extension showed a mean annual change in eGFR of −0.4 mL/min/1.73 m² over 54 months; and PHYOX3 maintained mean eGFR between 71.1 and 81.5 mL/min/1.73 m² over 42 months, with a fall in the annualised rate of stone events from 0.40 to 0.20 [77, 78, 83]. These results come from open-label extensions without a comparator group and do not yet allow the conclusion that kidney failure or oxalosis is prevented [20]. At the time of writing, the PNDS noted the absence of long-term data on clinical outcomes [16].

11.2. Objectives and frequency of follow-up

Follow-up is lifelong and aims to monitor adherence to lifestyle and dietary measures, particularly urine output, stone activity and risk of recurrence, kidney function and nephrocalcinosis, the complications of systemic accumulation, the complications of treatment and the family, school and socio-professional impact [16]. Most patients are seen in clinic every 3 to 6 months, with intervals of 1 to 3 months in unstable situations and up to 12 months in stable ones, depending on age, CKD stage and treatment [16]. The European consensus recommends that patients with PH should not be discharged from the clinic [20].

11.3. Surveillance table

Bone densitometry is of no value according to the PNDS; the PH2 GeneReviews regarded it as optional every 5 years in advanced CKD, a recommendation predating the European consensus [3, 16]. The overarching aim is to minimise investigations involving ionising radiation [16, 20]. The OHF proposes its own intervals by CKD stage, more frequent than those of the PNDS in CKD 5 (six-monthly eye examination and echocardiography), and includes bone imaging at diagnosis and thereafter as clinically indicated, whereas the European consensus reserves it for symptoms; it points out that the radiological findings of bone oxalosis may mimic secondary hyperparathyroidism and adynamic bone disease, that bone biopsy is not routine, that magnetic resonance imaging and peripheral quantitative computed tomography are techniques under study and that plasma FGF23 may be monitored [16, 20, 24]. The intervals on RNA interference are detailed in section 7 and coincide with those in this table: biochemical assessment every 3 to 6 months in the first year, then six-monthly for 3 to 5 years and then annually in CKD 1–3, and three-monthly in CKD 4, 5 and 5D [16, 20].

11.4. Follow-up after transplantation

Liver transplant recipients continue to release oxalate from deposits for many years, so metabolic follow-up should continue to be provided by a hyperoxaluria specialist [16]. Immediately after kidney transplantation, crystalluria is monitored several times a week, progressively less often after a few weeks, in parallel with urinary oxalate; conservative treatment (hyperdiuresis, pyridoxine and potassium citrate) is maintained while urinary oxalate remains above normal [16]. In patients on RNA interference, post-transplant follow-up includes 24-h urinary parameters (oxalate, citrate, calcium), spot crystalluria and adaptation of conservative treatment, including a thiazide diuretic when indicated [16]. The European consensus recommends measuring urinary and plasma oxalate at least six-monthly after liver transplantation until normal on three occasions, and at least six-monthly after kidney transplantation on pyridoxine or RNA interference until normal, and then at least annually [20]. The OHF proposes a tighter schedule [24].

The text of the best practices describes monthly plasma oxalate up to 6 months before moving to three-monthly, with stable values below 20 µmol/L, whereas the recommendations box indicates monthly only in months 2–4; in both cases, three-monthly monitoring continues indefinitely in patients on RNA interference or pyridoxine [24]. These intervals are more frequent than the six-monthly minimum of the European consensus [20, 24].

12. Summary and Final Considerations

The primary hyperoxalurias are three autosomal recessive disorders of hepatic glyoxylate and hydroxyproline metabolism that produce excess oxalate: PH1, due to deficiency of the peroxisomal alanine-glyoxylate aminotransferase encoded by AGXT, accounts for 70 to 80% of diagnosed cases and has the worst prognosis; PH2, due to deficiency of the cytosolic glyoxylate reductase/hydroxypyruvate reductase encoded by GRHPR, about 10%; and PH3, due to deficiency of the mitochondrial 4-hydroxy-2-oxoglutarate aldolase encoded by HOGA1, 10 to 20%, with exceptional kidney failure. The initial clinical presentation is indistinguishable between the three types and consists of recurrent calcium oxalate urolithiasis, nephrocalcinosis and progressive chronic kidney disease; most patients have their first symptom before the age of 5, but diagnosis may occur from the prenatal period to beyond 60 years, and half of patients with PH1 already have advanced kidney failure when diagnosed.

The clinical axis that determines severity is the glomerular filtration rate threshold of 30 mL/min/1.73 m²: below it, hepatic production exceeds renal elimination, plasma oxalate exceeds the supersaturation threshold and deposits in bone, heart, vessels, retina and thyroid, with refractory anaemia, fractures, cardiomyopathy, arrhythmias, neuropathy and skin ulcers. Infantile oxalosis, defined as end-stage kidney disease before 1 year and described only in PH1, still carries high, although falling, mortality.

Diagnosis rests on two measurements of acidified 24-h urinary oxalate, interpreted against age-specific reference values, on plasma oxalate when kidney function is below 30 mL/min/1.73 m², and on morphoconstitutional stone analysis, whose subtype Ic is almost specific for primary hyperoxaluria. Confirmation and typing are genetic and determine treatment. Exclusion of secondary causes, particularly enteric hyperoxaluria, precedes genetic investigation, and a negative study does not exclude an inherited hyperoxaluria, because up to 10% of clinically evident forms have no identified molecular cause.

Conservative treatment begins as soon as the diagnosis is suspected: hyperhydration of 3.5 to 4 L/day in adults and 2 to 3 L/m² in children, spread over 24 hours and often by gastrostomy in infants, potassium citrate as a crystallisation inhibitor, a normal-sodium diet with calcium at meals and avoidance of oxalate precursors, and a therapeutic trial of pyridoxine in all patients with PH1, starting at 5 mg/kg/day and continuing it in the approximately 30% who reduce urinary oxalate by more than 30%. RNA interference agents have changed the treatment of PH1: lumasiran, authorised in the European Union and the United States for all ages, and nedosiran, authorised only in the United States from 2 years of age with relatively preserved kidney function, reduce urinary oxalate in a sustained manner, with injection site reactions as the dominant adverse effect. The European consensus stratifies the indication into seven groups according to pyridoxine response, kidney function and clinical activity, and requires reassessment at month 6 and annually thereafter. Efficacy data on clinical outcomes come from open-label extensions without a comparator and show stable kidney function and fewer stone events up to 60 months, without demonstration of prevention of kidney failure or oxalosis. Neither lumasiran nor nedosiran has established efficacy in PH2 or PH3, whose treatment remains conservative and urological.

When kidney function has already been lost, no dialysis modality compensates for endogenous production, and intensified dialysis is a bridge to transplantation. Liver transplantation with removal of the native liver is the only cure for PH1, and combined liver-kidney transplantation has much better kidney graft survival than isolated kidney, except in patients homozygous for pyridoxine-responsive variants, in whom isolated kidney is an option. On RNA interference, isolated kidney transplantation has become possible, but experience is limited to reports and small series, and mobilisation of stored oxalate continues to threaten the graft. In PH2, isolated kidney is the usual treatment, with losses due to recurrence, and liver transplantation is a suggested option in advanced disease.

Surveillance is lifelong and organised by kidney function: urinary oxalate and kidney function every 3 to 12 months, renal ultrasound at least annually, analysis of all passed stones, and, from stage 4 or in the infantile form, annual fundoscopy, echocardiography and thyroid function, with plasma oxalate three-monthly to monthly. Adherence to hyperdiuresis is the main modifiable determinant of prognosis, and the transition from paediatric to adult medicine should be prepared. Genetic diagnosis of siblings is indicated at any age, even if asymptomatic, and prenatal and preimplantation diagnosis are possible once the familial variants have been identified. The remaining gaps are the treatment of PH2 and PH3, demonstration that targeted therapies prevent kidney failure and oxalosis, early assessment of systemic oxalosis, the diagnostic delay of decades in adults and inequalities of access to drugs and genetic diagnosis between regions.

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