Hereditary Renal Hypouricaemia (SLC22A12 and SLC2A9)

Hereditary proximal tubulopathy due to loss of urate reabsorption, with very low serum urate and high fractional excretion of urate; usually silent, it predisposes to acute kidney injury after anaerobic exercise and to urolithiasis.

Literature and regulatory information updated: 7 November 2026.

0. Initial Reference Table

1. Introduction

Hereditary renal hypouricaemia (RHUC) is an isolated proximal tubulopathy in which the kidney fails to reabsorb filtered urate. The biochemical result is very low serum urate, with urinary urate excretion inappropriately high for the serum value, without the other tubular losses that characterise Fanconi syndrome. The 2017 Japanese guideline, the first clinical guideline devoted to the disease, defines it as hypouricaemia caused by dysfunction of renal urate reabsorption and excludes from the concept inborn errors of purine metabolism, such as xanthinuria and purine nucleoside phosphorylase (PNP) deficiency, and secondary hypouricaemias, such as those associated with malignant tumours [10]. Orphanet groups the two genetic types under a single code, ORPHA:94088, defined as a genetic renal tubular disease with urinary urate loss, usually asymptomatic, that predisposes to urolithiasis and exercise-induced acute renal failure [2].

The first description of a patient with hypouricaemia due to tubular elimination of uric acid was published by Praetorius and Kirk in 1950; Greene and colleagues characterised in 1972 the hereditary form of isolated defect of tubular urate reabsorption, which they compared with the mutation of the Dalmatian dog; Akaoka and colleagues published the first Japanese case in 1975, according to the historical review of the Japanese guideline [10]. From the outset, the disease was recognised as relatively frequent in the Japanese and Jewish populations [10]. Akaoka's family had at least four affected individuals of both sexes, all children of consanguineous marriages, and Takeda and colleagues observed in 1985 that the ratio of urate clearance to creatinine clearance in the parents of affected children was intermediate between that of patients and normal values [1]. The analogy with the Dalmatian dog gained a molecular basis in 2008, when the hyperuricosuria of this breed was attributed to the missense variant p.Cys188Phe of the canine Slc2a9 gene, homozygous in the 247 Dalmatians tested and absent in 378 dogs from 58 other breeds; the animal model therefore corresponds to the RHUC2 transporter and not to URAT1 [6]. In 2002, Ishikawa gathered 118 cases of acute kidney injury with severe loin pain and patchy renal ischaemia after anaerobic exercise, designated by the acronym ALPE (acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise), and found that about half of the patients with known serum urate had renal hypouricaemia [17].

The molecular basis was identified in two stages. In 2002, Enomoto and colleagues identified the transporter URAT1, encoded by SLC22A12, as the urate-anion exchanger of the human proximal tubule that regulates serum urate and is the target of uricosuric drugs, and demonstrated SLC22A12 defects in patients with idiopathic renal hypouricaemia [18]. In 2008, Matsuo and colleagues described loss-of-function variants in SLC2A9, which encodes the transporter GLUT9, in Japanese patients without SLC22A12 variants [19], in the same year in which genome-wide association studies showed that common SLC2A9 variants determine part of the population variation in serum urate [20]. In 2010, Dinour and colleagues demonstrated that homozygosity for loss-of-function variants of SLC2A9 causes a total reabsorption defect, with mean serum urate of 0.17 mg/dL and FEUA above 150% [14].

The nomenclature in use distinguishes renal hypouricaemia type 1 (RHUC1, OMIM 220150), caused by biallelic SLC22A12 variants, from renal hypouricaemia type 2 (RHUC2, OMIM 612076), caused by SLC2A9 variants [1, 3, 10]. OMIM also retains two phenotypic entries without a confirmed molecular basis, hypouricaemia with hypercalciuria and decreased bone density (242050) and familial renal hypouricaemia due to tubular hypersecretion (307830), which Orphanet integrates under the same code as narrower concepts [2, 21, 22]. The first rests on a single family described by Sperling in 1974, with markedly increased renal urate clearance in three siblings and in two grandchildren, children of a marriage between first cousins who were obligate heterozygotes [21]. The second corresponds to a fourth functional type, described by Shichiri (1982), Dumont and Decaux (1983) and Sanz (1983), in which the urate clearance response to probenecid and pyrazinamide is normal or exaggerated and the hypouricaemia is attributed to tubular hypersecretion with intact reabsorption; familial occurrence was described by Nakajima in 1987 in two siblings with hypouricaemia, whose mother had serum urate at the lower limit of normal, the proband being a 36-year-old man with a 48,XXYY karyotype and the other relatives having a normal karyotype [22]. Neither entry has an associated gene in OMIM [21, 22]. The older literature classified patients by patterns of response to pyrazinamide and probenecid into «presecretory» and «postsecretory» reabsorption defects; the study by Wakida and colleagues showed that the presecretory type corresponds to URAT1 variants, whereas a family with the postsecretory type had no variants in the gene [23]; Gafter and colleagues had proposed in 1989 the combined pyrazinamide-probenecid test to separate presecretory, postsecretory and combined defects from hypersecretion with intact reabsorption [1], and Sperling interpreted the blunted response in these tests as a consequence of the loss of URAT1, the target of both drugs [24]. A proportion of patients with a typical phenotype have no variants in the two known genes, which points to genes not yet identified or to variants not detected by the methods used [7, 10].

The disease lies at the intersection of nephrology, sports medicine and disorders of purine metabolism. Saudubray includes it among the defects of uric acid transport in the chapter on purine disorders with urolithiasis or renal involvement [25], and the French national diagnosis and care protocol (PNDS) for paediatric urolithiasis states that these families tend to present with episodes of acute renal failure rather than with stone disease [26]. The clinical value of the diagnosis lies in the two complications and in the possibility of preventing them with simple measures, once a low serum urate, which often goes unnoticed in routine tests, has been recognised [7, 10].

2. Molecular Genetics and Pathophysiology

2.1. Renal physiology of urate

Urate is the end product of purine catabolism in humans, because hominids lost uricase, whose gene became a pseudogene during evolution [10]. Daily production is about 700 mg, mainly hepatic; two thirds are eliminated by the kidney and one third by extrarenal routes, such as the gut [10]. Uric acid is poorly soluble and tends to crystallise when the plasma concentration exceeds 6.5–7.0 mg/dL (0.38–0.47 mmol/L) [25]. All plasma urate is filtered at the glomerulus and about 90% of filtered urate is reabsorbed in the proximal tubule, so that only 6–10% of the filtered load appears in the urine; it is this reabsorptive efficiency that determines final excretion and serum urate [10, 11]. Saudubray describes distal urate secretion as competitive with organic acids such as lactate, methylmalonate and propionate, which explains secondary hyperuricaemias in organic acidaemias and hyperlactataemias [27].

The transcellular transport model proposed by Anzai and colleagues, taken up by the Spanish cohort, places URAT1 in the apical membrane, where it reabsorbs urate from the lumen in exchange for intracellular monocarboxylate anions, and GLUT9 in the basolateral membrane, where it mediates the exit of reabsorbed urate into the interstitium and the blood [9]. URAT1 is an electroneutral urate/monovalent anion exchanger (lactate, nicotinate, chloride) and the main determinant of the fraction of filtered urate that the kidney returns to the blood [28]. It is a 555-amino-acid protein with 12 transmembrane domains, expressed in the luminal membrane of the proximal tubule and not in the distal tubule; in Xenopus oocytes, urate uptake is inhibited by organic anions (lactate, nicotinate, acetoacetate, hydroxybutyrate, succinate) and by benzbromarone, probenecid, phenylbutazone, sulfinpyrazone, non-steroidal anti-inflammatory drugs and diuretics, but not by para-aminohippurate [4]. In the mouse, loss of the Na⁺/lactate cotransporters Slc5a8 and Slc5a12 increases uricosuria without altering Urat1 expression, which suggests that apical lactate reabsorption provides the anion that is exchanged for urate [4]. GLUT9 belongs to the family of facilitative hexose transporters, but in humans it functions mainly as a high-capacity, voltage-dependent urate transporter, moving urate 45 to 60 times faster than glucose [9, 29, 30]. The SLC2A9 gene produces two isoforms through alternative promoters that differ only in the amino-terminal tail: the long isoform GLUT9L (540 amino acids, 12 exons), in the basolateral membrane of the proximal tubule, and the short isoform GLUT9S (512 amino acids), in the apical membrane of the collecting duct [9, 31]. Matsuo and colleagues showed that both isoforms transport urate with high activity and proposed that GLUT9 variants reduce reabsorption on both sides of the tubular cell [19]. The SLC2A9 gene has 14 exons, including two alternative first exons with their own promoters, and spans about 215 kb; the urate transport activity of GLUT9 is sodium-independent, sensitive to membrane potential and increases at low extracellular pH [6]. The Glut9 knockout mouse is born at about half the expected Mendelian frequency and has moderate hyperuricaemia, massive uricosuria, a urinary concentrating defect and progressive chronic tubulointerstitial nephritis with cortical atrophy and hydronephrosis, attributed to tubular urate precipitation; liver-only inactivation causes severe hyperuricaemia and hyperuricosuria without renal injury [6]. The hyperuricaemia of this murine model contrasts with the hypouricaemia of human RHUC2 [3, 6]. The Japanese guideline adds the excretory transporter ABCG2 as the third main regulator of serum urate [10].

2.2. Mechanism of hypouricaemia and differences between the two types

Loss of function of URAT1 or GLUT9 increases urinary urate excretion and lowers serum urate; this is the basic mechanism of renal hypouricaemia [10]. The two types differ in the severity of the defect. In RHUC1, FEUA generally lies between 30% and 70%; in RHUC2, it frequently exceeds 100%, especially in homozygotes [10]. The explanation proposed by Dinour and colleagues is that apical urate uptake depends not only on URAT1 but also on other apical transporters, such as OAT4, OAT10 and GLUT9S, whereas basolateral exit depends only on GLUT9L; complete loss of URAT1 produces a partial defect, with FEUA of 40% to 90%, and complete loss of GLUT9 blocks the exit of all urate entering the cell, with a total reabsorption defect and FEUA above 100% [9, 31]. A FEUA above 100% indicates that the kidney eliminates more urate than it filters, which implies a secretory component; Dinour's work in Iraqi Jews further showed that URAT1 itself facilitates urate efflux, which is abolished in the mutant forms [32]. In patients with biallelic SLC22A12 variants, the CUA/Ccr (ratio of urate clearance to creatinine clearance) no longer responds to pyrazinamide, benzbromarone and probenecid, which confirms in vivo that URAT1 is the target of these drugs [33].

Potent uricosurics serve as a pharmacological model of the disease. Lesinurad increases FEUA to more than 30%, a value similar to that of homozygotes for non-functional URAT1 variants, and causes nephrotoxicity, more frequent in patients with high baseline serum urate who are not taking a xanthine oxidoreductase inhibitor, with recovery that can take up to three months; verinurad behaves similarly [11]. Dotinurad and benzbromarone increase FEUA by less than 10% and do not cause renal toxicity [11]. These data suggest that a tubular urate load of the order observed in homozygous RHUC can, in itself, injure the kidney [11].

2.3. Pathophysiology of exercise-induced acute kidney injury

The mechanism of exercise-induced acute kidney injury (EIAKI) has not been elucidated and several hypotheses coexist, which are not mutually exclusive. The first is vascular: loss of the antioxidant effect of plasma urate, in a setting of oxygen radical production by xanthine oxidase during anaerobic exercise, would favour renal vasoconstriction and patchy ischaemia [10]. It is supported by the reversible resistive index on renal Doppler, the wedge-shaped contrast retention on delayed computed tomography (CT), observed in 46 of 50 patients with ALPE studied with this technique, and wedge-shaped ischaemic lesions on diffusion-weighted magnetic resonance imaging [10, 17]. In hypouricaemia, the Japanese guideline reports frequent endothelial dysfunction in patients with serum urate ≤0.8 mg/dL, all homozygous for URAT1 variants [10], and other authors propose loss of nitric oxide-dependent and endothelium-derived hyperpolarising factor-dependent vasodilatation [34].

The second hypothesis is tubular: the filtered urate load increases during and after exercise and, without reabsorption, reaches the lumen at high concentration. The patient studied by Yeun and Hasbargen in 1995 increased urinary urate excretion from 0.48 to 1.49 mg/min four hours after an exercise test and developed acute kidney injury, whereas four controls did not change their excretion or renal function [35]. In the mouse with combined inactivation of Urat1 and uricase and with increased hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity, forced swimming to exhaustion increases creatinine, urea and urinary urate excretion, activates the NLRP3 inflammasome with release of interleukin 1β and reduces renal Na⁺-K⁺-ATPase; allopurinol and topiroxostat prevent these changes [36]. Interleukin 1β could activate sympathetic nerves that constrict the afferent arterioles and intrarenal sensory nerves responsible for loin pain [37]. The crystal obstruction hypothesis is less likely: biopsies show acute tubular necrosis without the crystalline spaces with inflammatory infiltrate of acute urate nephropathy, and in Mazzierli's patient the concentration of undissociated uric acid remained below the solubility limit [10, 37].

The third hypothesis is metabolic: after ischaemic forearm exercise, patients with RHUC have lower blood hypoxanthine, higher fractional clearance of hypoxanthine and lower erythrocyte adenosine triphosphate (ATP) than controls, which suggests loss of substrate for the purine salvage pathway and ATP depletion in the tubule [37, 38]. Isolated hypouricaemia does not appear sufficient to cause injury: almost all episodes have a trigger, such as anaerobic exercise, dehydration or gastroenteritis, and Mazzierli's review interprets the injury as the result of several factors acting on a biallelic genetic background [37].

2.4. Variant spectrum, nomenclature and founder variants

The Human Gene Mutation Database (HGMD) listed, in March 2023, 64 SLC22A12 variants associated with RHUC1 (34 missense) and 34 SLC2A9 variants associated with RHUC2 (14 missense) [9]. Most of the URAT1 variants studied reduce urate uptake in Xenopus oocytes; several, such as p.Gly366Arg, p.Thr467Met and the in-frame three-amino-acid deletion, cause misfolding with retention of the protein in the endoplasmic reticulum [39]. The following table gathers recurrent or historically important variants, normalised in VariantValidator on the MANE Select transcripts (Matched Annotation from NCBI and EMBL-EBI; GRCh38) and with the ClinVar classification when consulted.

Three nomenclature points should be noted. The Roma deletion, published as p.L415_G417del, is normalised by VariantValidator as p.(Ala416_Leu418del), because the 3′ alignment rule shifts the in-frame deletion; both describe the same genomic change, NC_000011.10:g.64599850_64599858del [5]. SLC2A9 numbering varies with the isoform: the MANE Select transcript is NM_020041.3 (GLUT9L), and the short isoform NM_001001290 has 29 fewer amino acids, so that p.Arg380Trp corresponds to p.Arg351Trp and p.Gly216Arg to p.Gly187Arg in the short isoform [5, 31]; a Korean report also uses the short-isoform numbering as primary (p.Met126Val in GLUT9b, p.Met155Val in GLUT9a) [50]. Finally, the designation «G774A», used in several Japanese series, describes the same variant as c.774G>A p.(Trp258Ter) [33, 34]. Some OMIM descriptions do not match current normalisation: p.Thr125Met appears as c.375C>T, but VariantValidator indicates that position c.375 of NM_020041.3 is a guanine and that the correct substitution is c.374C>T; p.Pro412Arg appears as 1296C>G, a numbering that does not correspond to the coding sequence (c.1235C>G in dbSNP rs121908323); and the insertion in the Czech siblings is described as Ile118HisfsTer27, normalised as c.354dup p.(Ile119HisfsTer27) [5, 6].

The distribution of variants reflects founder effects. The W258X allele derives from a single haplotype with an estimated age of about 6,820 years (95% confidence interval 1,860 to 11,760 years), predating the Yayoi migration from the Korean peninsula to Japan, and is also the most frequent mutant allele in Korea [11, 51]. The two Roma variants have different frequencies across subisolates, owing to genetic drift, and T467M appears to have originated in South Asia, where gnomAD records the highest frequency (0.70%) [12]. In Spain, SLC2A9 c.374C>T lies on a haplotype shared by the Spanish patients and by the Israeli patient of Sephardi origin in whom it was described, which led the authors to propose an origin in the Sephardi population of the Iberian Peninsula [9]. Nine Greeks with primary renal hypouricaemia had no SLC22A12 variants, which illustrates genetic heterogeneity in European populations [52].

2.5. Inheritance, allele dosage and penetrance

RHUC is classically described as autosomal recessive, but OMIM records both recessive and dominant patterns for RHUC2, Orphanet mentions both and several series describe mild phenotypes in heterozygotes for both genes [2, 3, 7, 37]. Population data show a continuous allele dosage effect. In 2,240 Japanese individuals with FEUA available, mean FEUA with zero, one and two non-functional URAT1 alleles was 3.94%, 6.57% and 42.6% in men and 5.37%, 6.43% and 45.9% in women; mean serum urate was 6.10, 4.17 and 0.75 mg/dL in men and 4.56, 3.31 and 0.65 mg/dL in women [8]. The Japanese guideline, citing Sakiyama, reports that carrying W258X or R90H in the heterozygous state, or two alleles, lowers mean serum urate from 6.2 to 4.0 or 0.8 mg/dL in men and from 4.5 to 3.5 or 0.6 mg/dL in women [10]. In the Galician cohort, 18 of 24 monoallelic carriers had abnormal serum urate, 14 of whom had mild hypouricaemia (2.05–3.3 mg/dL) and FEUA of 9.7% to 13.4%; serum urate and FEUA differed between zero, one and two alleles (P=9.96×10⁻⁴ and P=0.0060) [7].

In RHUC2, heterozygosity has a greater effect. Spanish heterozygotes for p.Thr125Met had serum urate of 1.0–1.9 mg/dL and FEUA of 19% to 39%, versus 0.12–1.20 mg/dL and 41% to 190% in homozygotes [9]; the first Japanese patients with RHUC2 were heterozygous for R380W and R198C [19], and Dinour attributed the heterozygote phenotype to haploinsufficiency [9]. In the Israeli Arab family with p.Leu75Arg, FEUA was above 150% in homozygotes, 13% in heterozygotes and 8.4% in non-carriers [6]. The heterozygous effect is not constant: the heterozygous parents of the three siblings with p.Arg171Cys and the heterozygous parents and sibling of the Czech patients had normal serum urate and FEUA, which OMIM records as discordant with the Japanese report of hypouricaemia in heterozygotes and attributes to other genetic or non-genetic factors [3, 6]. Conversely, a heterozygous SLC2A9 nonsense variant did not cause severe hypouricaemia in the relatives of Shima's patient, who was a compound heterozygote [53]. The biochemical penetrance in heterozygotes is incomplete: three relatives of a Galician proband who were heterozygous for p.Thr467Met had normal serum urate and FEUA [7]. Complications cluster in biallelic genotypes: in the review of 40 patients with acute kidney injury, the 23 with genetic testing were all biallelic [37], although EIAKI has been described in some heterozygotes [11].

2.6. Modifiers and distinction from common variants

Sex is the most studied modifier. Female sex hormones increase renal urate excretion, so that heterozygous women have lower serum urate than heterozygous men; this explains why the prevalence of serum urate ≤2.0 mg/dL is two to three times higher in women, and higher before menopause, whereas the prevalence of serum urate ≤1.0 mg/dL, almost always biallelic, is similar in both sexes [10, 11]. Other described modifiers are ABCG2 variants, which alter the renal urate load [11], thiazides, which raise serum urate, a 17q12 deletion including HNF1B, which tends towards hyperuricaemia, and concomitant Gitelman syndrome, which complicate biochemical interpretation in carriers [7]. The Slovak Roma cohort also had concomitant founder diseases, such as phenylketonuria and short-chain acyl-CoA dehydrogenase deficiency [12].

Mendelian RHUC2 must be distinguished from the association of common SLC2A9 variants with serum urate. In a genome-wide association study, common SLC2A9 variants explained 1.7% to 5.3% of the variance in serum urate and were associated with lower fractional excretion and with gout [20]; a common urate-associated allele is not a diagnosis of RHUC and does not confer the risk of EIAKI [29]. OMIM records this association as a quantitative trait locus (UAQTL2) and as susceptibility to gout (GOUT2) in the same entry 612076 [3]. In the association studies, the effect per minor allele ranged from −0.23 to −0.36 mg/dL in the German KORA cohort, the proportion of variance explained was greater in women (about 6% versus 1.2% in men) and the allele associated with higher serum urate increased the risk of gout [3]. Common SLC2A9 missense variants, such as p.Gly25Arg, p.Val282Ile, p.Arg294His and p.Pro350Leu, found in the Slovak cohort, do not alter expression, localisation or urate uptake [12].

3. Clinical Spectrum and Manifestations by System

3.1. Asymptomatic form and incidental discovery

Renal hypouricaemia is, in most people, an isolated laboratory finding. The Japanese guideline states that most cases are discovered by chance in routine tests and that the disease itself is asymptomatic, its hallmark being the combination of low serum urate with increased renal urate excretion [10]. In the Spanish clinical series, 14 of 21 patients were asymptomatic and renal function was normal in all [9]; in the Slovak Roma cohort, none of the nine probands had clinical or laboratory signs of kidney disease [12]. The Orphanet phenotype table considers hypouricaemia and hyperuricosuria obligatory and lists, with a frequency of 30% to 79%, acute kidney injury, uric acid urolithiasis independent of gout and abnormalities of tubular morphology and physiology; with a frequency of 5% to 29%, haematuria, nausea and vomiting, hypercalciuria, loin pain, mild proteinuria, decreased glomerular filtration rate (GFR) and chronic kidney disease (CKD) [2]. These frequencies reflect published series, enriched for symptomatic patients, and not the carrier population.

The testimony of a professional mixed martial arts fighter, published as an appendix to the Japanese guideline, describes nausea after short runs and sports events since primary school and repeated episodes of vomiting and malaise, with difficulty eating for weeks, after bouts preceded by weight cutting; the symptoms were attributed for years to lack of warm-up or preparation [10]. This account illustrates that mild episodes can pass for exercise intolerance.

3.2. Exercise-induced acute kidney injury

EIAKI is the complication that gives the disease its clinical relevance. The Japanese guideline defines it as acute kidney injury with loin pain, without (or with only a mild) increase in creatine kinase (CK) and myoglobin, after brief, intense, anaerobic exercise, such as sprinting, football, weight training, cycling or weightlifting; patients had often taken anti-inflammatory drugs for cold symptoms [10]. The symptoms, similar to those of renal colic (loin pain, nausea and vomiting), appear 1 to 48 hours after exercise; dehydration is less marked than in myoglobin-induced injury, the form is usually non-oliguric and without rust-coloured urine, CK and myoglobin do not exceed about nine and seven times the upper limit of normal, and the mean duration is 14 days [10]. The median age at onset is 19 years and the male:female ratio 202:18 [10].

The Japanese national survey by Ohta and colleagues gathered 54 patients (48 men, 6 women) from 38 institutions: the median age at the first episode was 17 years (11–46), the peak serum urate during the episode 4.40 ± 2.49 mg/dL (0.4–13.3), the peak creatinine 5.45 ± 3.33 mg/dL (1.10–17.7) and serum urate after recovery 0.70 ± 0.25 mg/dL [13]. Episodes occurred mainly in September, October and May, after strenuous exercise such as short-distance races; the first symptoms were nausea or vomiting in 51 episodes, loin pain in 35, abdominal pain in 22, fatigue in 16 and low-grade fever in 7 [13]. Histology, available in 28 patients, showed minimal changes or acute tubular necrosis, except in one patient with chronic lesions [13]. In Ishikawa's review, creatinine was 4.7 ± 2.9 mg/dL at first presentation and 6.0 ± 3.0 mg/dL at peak, and 20 of 109 patients required dialysis [17].

The review of 40 patients published between 1974 and 2022 with renal hypouricaemia and acute kidney injury, coordinated by Mazzierli, quantified the typical picture: 90% were men, 93% of Asian ancestry and the median age was 18 years; 92.5% had never had a uric acid measurement; there was a trigger (exercise or gastroenteritis) in 95%; loin pain in 97%, nausea or vomiting in 87.5%, hypertension in 40%, oligoanuria in 27.5%, fever in 12.5% and extrarenal manifestations (acute pulmonary oedema, posterior reversible encephalopathy, hyperbilirubinaemia) in 22.5% [37]. Median creatinine was 4.7 mg/dL, with only moderately raised urea (median 50 mg/dL), no electrolyte abnormalities, proteinuria in 48% and haematuria in 23%, median CK of 223 IU/L and, counter-intuitively, median serum urate of 4 mg/dL in the acute phase, with median FEUA of 66% [37]. Renal biopsy was performed in 40%, dialysis in 22.5% and the median hospital stay was 14 days; 77.5% recovered with supportive care alone [37].

Normal serum urate during the acute injury is a central point in diagnosis. With the fall in GFR and the muscular release of purines, serum urate rises to normal values and only falls to the patient's usual level during recovery, while estimated GFR rises; the Japanese guideline therefore recommends measuring uric acid before the episode, if previous results exist, or after recovery [10, 37]. In Aizawa's adolescent footballer, serum urate was 6.8 mg/dL with creatinine of 7.04 mg/dL and fell to 0.9 mg/dL after recovery, with FEUA of 48% to 62% [38]. There are reports of EIAKI after exercise of moderate intensity: an Indian man with RHUC2 had three years of recurrent episodes of self-limiting acute kidney injury with haematuria, practising only 60 minutes a day of moderate aerobic and strength exercise [54].

Recurrence is frequent. Tanaka and colleagues described two Japanese brothers homozygous for W258X: the proband, aged 45, had abdominal pain, vomiting, loin pain and oliguria after a strenuous run, and both reported similar episodes once or twice a year since the age of 20; serum urate was 0.8 and 1.0 mg/dL, FEUA 46% and 65.7%, and both had bilateral urolithiasis; the parents and the five children of the two brothers were heterozygous [1]. In the Japanese guideline, 43 of 221 cases (19.5%) recurred [10]; in Ohta's survey, 13 of 54 patients (24.1%) had repeated episodes, with no risk factor identified, and no woman had a recurrence [13]; in Mazzierli's review, among patients with described follow-up, 60% had at least one relapse, all in patients with a genetic diagnosis, which the authors attribute to closer follow-up after confirmation [37].

3.3. Posterior reversible encephalopathy and other acute complications

Posterior reversible encephalopathy syndrome (PRES) has been described in association with EIAKI. Shima and colleagues described a Japanese girl with severe RHUC2 (serum urate 0.1 mg/dL), compound heterozygous for a nonsense variant and a large duplication of SLC2A9, with recurrent episodes of EIAKI complicated by PRES, and considered a specific relationship with GLUT9 [53]. Fujinaga and colleagues later described a 13-year-old boy with RHUC1 homozygous for W258X, serum urate 0.9 mg/dL, volume overload (11 kg above dry weight) and blood pressure of 153/88 mmHg, with occipital cortical and subcortical hyperintensities on magnetic resonance imaging, treated with haemodialysis and intravenous nicardipine; the authors concluded that PRES is a manifestation of severe EIAKI, and not of profound hypouricaemia due to SLC2A9 [55]. Other acute manifestations described in series are acute pulmonary oedema and hyperbilirubinaemia [37].

3.4. Urolithiasis

The high urate load in the tubular lumen predisposes to stones. In Ichida's series, four of 32 patients (12.5%) had urolithiasis and three (9.4%) EIAKI [33]; in another Japanese series cited by the guideline, six of 71 patients (8.5%) had urolithiasis, four of 43 men and two of 28 women, and a national survey found 11 of 179 (6.1%) [10]. In Sugihara's retrospective series, four of 13 patients (30.8%) had urolithiasis, almost all with two null URAT1 alleles and CUA/Ccr of 44% to 74% [34]. The guideline acknowledges that the real figures are higher if asymptomatic stones are counted and that urolithiasis should be more frequent in RHUC2, owing to the higher tubular concentration [10]. A review cited by Stiburkova estimates that the prevalence of stones is six to seven times higher in RHUC than in normouricaemic individuals [12]. Stones may be of uric acid or calcium oxalate, pure or mixed with uric acid; for calcium oxalate stones, heterogeneous nucleation on a uric acid nidus and the salting-out effect of dissolved urate have been proposed [10]. Hypercalciuria was found in three of five Chinese patients with nephrolithiasis [49], and an OMIM entry without a molecular basis describes the association of hypouricaemia, hypercalciuria and decreased bone density [21]; a case of renal hypouricaemia with absorptive hypercalciuria had raised plasma 1,25-dihydroxyvitamin D [56]. Orphanet adds haematuria, pyelonephritis and nephrocalcinosis to the complications of chronic urate loss [2].

3.5. Long-term renal function and systemic associations

Long-term renal outcome is poorly known and studies give divergent results. The Japanese guideline states that there are no reports of patients with EIAKI who progressed to chronic dialysis [10]. In Japanese population studies, serum urate ≤2.0 mg/dL was associated with a higher prevalence of estimated GFR below 60 mL/min/1.73 m² in men, but not in women, and the W258X allele was independently associated with lower estimated GFR in two cohorts [10, 11]. In the largest study, with 450,204 participants from health screening in Shizuoka and a mean follow-up of 6.1 years, hypouricaemia was associated with lower baseline estimated GFR and with rapid decline in renal function (≥3 mL/min/1.73 m² per year; adjusted odds ratio 1.59; 95% confidence interval 1.08–2.28), but not with cardiovascular events (hazard ratio 0.74; 0.39–1.43) or all-cause mortality (1.25; 0.90–1.73) [57]. In this study, hypouricaemia was defined by screening tests, without genetic confirmation. In contrast, Sugihara's pilot study, with 13 patients and seven followed for four years, found no difference in annual decline in estimated GFR compared with 31 matched normouricaemic controls (−1.09 ± 1.11 versus −1.09 ± 1.92 mL/min/1.73 m² per year) [34]. Mazzierli's review notes that repeated acute kidney injury may lead to progressive decline in GFR and that the relationship between hypouricaemia and CKD has only been observed in men [37]. In the Spanish cohorts, some patients had progressive deterioration of renal function, rapidly progressive glomerulonephritis or nephrotic syndrome, with no established causal relationship [9, 58]. A 69-year-old Japanese woman with RHUC1 had CKD G3b and a renal stone [59].

Saudubray states that urate transporter defects may predispose to Parkinson's disease [27], and the Japanese guideline describes endothelial dysfunction in patients with very low serum urate [10]; the sources consulted do not quantify these risks in patients with a genetic diagnosis.

3.6. Differences between the two types and by age

Homozygotes and compound heterozygotes for SLC2A9 have the most severe biochemical form, with mean serum urate of 0.15–0.17 mg/dL and FEUA of 89% to more than 150% [14, 15]. Biochemical severity does not by itself determine complications: in Dinour's two families with homozygous p.Arg171Cys and p.Thr125Met, none of the four affected individuals had urolithiasis or EIAKI [15], whereas in the family with p.Leu75Arg three had urolithiasis and three a history of EIAKI [14]. In Iraqi Jews with homozygous RHUC1 (serum urate 0.5–0.8 mg/dL; FEUA 50–85%), most were asymptomatic, two had urolithiasis and none EIAKI [32]. In a Chinese cohort of 19 patients, 10 presented with EIAKI and five with nephrolithiasis, with a favourable renal outcome [49]. In childhood, EIAKI is described mainly in adolescence, from the age of 11 years [13]; two British boys aged 12 and 14 with RHUC2 had acute kidney injury [47]. Paediatric urate physiology must be taken into account: in the first months of life serum urate is low (131–149 µmol/L at 2–3 months) owing to FEUA above 10%, which falls to about 8% at one year of age [12].

4. Clinical Recognition and Warning Signs

4.1. Low serum urate on a routine test

The most common situation is a low serum urate on a health check. The Japanese guideline strongly recommends that every person with serum urate ≤2.0 mg/dL (120 µmol/L) be considered for differential diagnosis of hypouricaemia [10]. Between 2.1 and 3.0 mg/dL (121–180 µmol/L) mild RHUC may be present, and the guideline advises repeating the measurements and asking about family history, especially if there is a history of EIAKI, urolithiasis or relatives with hypouricaemia [10]. The Japanese J-MICC cohort showed that, in men with serum urate ≤3.0 mg/dL, the W258X allele was the only risk factor identified, and the authors propose suspecting RHUC at this threshold, especially in men [60]; the Galician cohort proposes investigating FEUA when serum urate remains below about 3 mg/dL on repeated measurements [7]. Serum urate values ≤1.0 mg/dL point to RHUC or xanthinuria [10].

Interpretation depends on reference values by age and sex. Saudubray gives normal serum urate values of about 300 µmol/L (5.0 mg/dL) in men, 240 µmol/L (4.0 mg/dL) in women and 180–240 µmol/L (3–4 mg/dL) in children [27]. A low serum urate is often ignored in laboratory reports because it lies within, or close to, the lower reference limit, and FEUA is rarely requested [7].

4.2. Acute kidney injury in a young person after exercise

The second setting is acute kidney injury in an adolescent or young adult, almost always male, occurring hours to two days after intense anaerobic exercise, such as sprinting, football, basketball, cricket, weight training or combat sports [10, 31, 37]. The warning signs described in Mazzierli's review are male sex, Asian ancestry, prodromes of loin or flank pain and nausea or vomiting after a trigger, markedly raised creatinine with only moderately increased urea, absence of electrolyte abnormalities, mild urinary abnormalities and an increased FEUA with normal serum urate [37]. Normal or slightly raised CK distinguishes EIAKI from rhabdomyolysis-induced injury [10]. Use of non-steroidal anti-inflammatory drugs (NSAIDs) for pain or flu-like symptoms is frequent before deterioration [10, 38]. A repeated episode of «renal colic» without a stone after exertion, a family history of similar episodes or of hypouricaemia and the finding of very low serum urate after recovery strengthen the suspicion [31, 38].

4.3. Uric acid urolithiasis with low serum urate

A uric acid stone, or a mixed calcium oxalate stone, in a person with low serum urate should prompt measurement of FEUA. Uric acid stones are radiolucent and therefore do not appear on plain radiography; ultrasound and especially non-contrast CT are the appropriate examinations [10]. Saudubray's tables include hereditary renal hypouricaemia among the hereditary causes of urolithiasis by stone composition (uric acid) [27].

4.4. Other settings

Renal hypouricaemia may be discovered during the assessment of living kidney donors: an Indian donor had serum urate of 0.3 mg/dL and FEUA of 95% [45]. It may also be found in patients with other kidney diseases, in whom it alters interpretation: a 55-year-old Roma woman with rapidly progressive glomerulonephritis had serum urate of 6.5 mg/dL in the acute phase and evident hypouricaemia only after renal function normalised [9]. There is no newborn screening for the disease.

4.5. Emergency signs

Signs of severity in EIAKI are oligoanuria, hyperkalaemia or other electrolyte disturbance, volume overload with hypertension or pulmonary oedema, uraemia and neurological symptoms (headache, visual disturbances, seizures), which should raise the possibility of PRES [10, 37, 55]. In these situations, the Japanese guideline states that haemodialysis is indicated [10].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The 2017 Japanese guideline proposes diagnostic guidance based on simple blood and urine tests, which does not require genetic testing [10]. Orphanet reproduces these criteria, with a FEUA threshold above 10% and the requirement of two consecutive measurements of serum urate below 2 mg/dL [2].

Source: Japanese guideline, Table 1 [10].

The thresholds have genetic support. In the J-MICC cohort of 4,993 Japanese individuals, nine of ten people with serum urate ≤2.0 mg/dL had W258X or R90H, and in multivariate analysis only these variants remained associated with hypouricaemia (odds ratio per allele of 550.5 for R90H and 302.8 for W258X), whereas sex, age and body mass index no longer had an independent effect [60]. Conversely, the 2.0 mg/dL threshold does not capture monoallelic carriers with mild hypouricaemia: in Galicia, carriers generally had serum urate of 2 to 3.3 mg/dL with FEUA above 10% [7], and Japanese authors estimate that, with serum urate between 2.0 and 3.0 mg/dL, at least two thirds of men and one third of women carry a non-functional allele [8]. The Japanese guideline considers repeat testing in this range desirable [10], and Sugihara's study used as an operational definition serum urate ≤3 mg/dL with CUA/Ccr above 10% [34].

5.2. Calculation of fractional excretion and collection method

FEUA is the ratio between uric acid clearance and creatinine clearance and is calculated as (urinary uric acid × serum creatinine) / (serum uric acid × urinary creatinine) × 100 [60]. It can be obtained from a spot urine sample, preferably fasting and repeated; a timed collection is preferable for CUA, which depends on urine volume [10]. The guideline describes the 60-minute method of the Japanese guideline on hyperuricaemia and gout: restriction of purine-rich foods and alcohol on the three preceding days; on the day of the test, fasting and two glasses of water on waking; 30 minutes before the start, 300 mL of water; at minute zero, voiding to empty the bladder; at 30 minutes, blood sampling for uric acid and creatinine; at 60 minutes, collection of all urine for volume, uric acid and creatinine [10]. Normal urinary urate excretion is 0.496 (0.483–0.509) mg/kg/h and is normal or slightly increased in RHUC [10]; in 24-hour urine, the Japanese urolithiasis guideline defines hyperuricosuria as above 800 mg/day in men and 750 mg/day in women [10], and the European urolithiasis guideline as above 5 mmol/day in men, 4 mmol/day in women and 0.12 mmol/kg/day in children [61].

Reference values for FEUA vary with age and sex. The Slovak cohort used ranges of 5% to 20% below 13 years, 5% to 12% in men and 5% to 15% in women [12], and Mazzierli's Italian case used 4% to 8% [37]. In the first months of life, physiological FEUA is above 10% [12], so hypouricaemia in infants is interpreted with caution.

5.3. Interpretation of FEUA and estimation of genotype

FEUA, together with serum urate, allows an approximate prediction of the number of affected alleles. In RHUC1 with two non-functional alleles, mean FEUA lies between 42% and 46% in Japanese population series [8] and between 30% and 70% in clinical series [10]; most patients with EIAKI have FEUA above 30% [11]. A FEUA above 100% suggests biallelic RHUC2 [10, 31]. Monoallelic carriers have slightly increased FEUA, which overlaps with the normal range, so biochemistry does not reliably identify heterozygotes [8, 11]. In the review of patients with acute kidney injury, median FEUA was 77% in cases with genetic confirmation and 56% in cases with a clinical diagnosis [37].

During acute kidney injury, serum urate is usually normal and FEUA is the only parameter that suggests the defect; FEUA is increased in any kidney injury with markedly reduced GFR, so its diagnostic value is greater when it is very high or repeated after recovery, when serum urate falls to baseline [10, 37]. In Aizawa's adolescent, FEUA was 62% in the acute phase and 48% to 56% afterwards, with serum urate of 0.9–1.1 mg/dL [38].

5.4. Ancillary investigations

Exclusion of generalised tubulopathy requires urinalysis (specific gravity, pH, protein, glucose and blood), urinary β2-microglobulin and N-acetyl-β-D-glucosaminidase (NAG), serum phosphate and acid–base status [10]. Exclusion of other causes of hypouricaemia is guided by the clinical picture: caeruloplasmin when Wilson disease is suspected, aminoaciduria and hypophosphataemia in Fanconi syndrome, serum sodium in SIADH (syndrome of inappropriate antidiuretic hormone secretion), blood glucose in diabetes and review of medication [10]. In hypouricaemia with near-zero urinary urate excretion, measurement of urinary hypoxanthine and xanthine points towards xanthinuria or molybdenum cofactor deficiency [25, 62].

When urolithiasis is suspected, CT is the most useful examination and the first choice in the emergency setting; ultrasound detects stones in the kidney, the proximal ureter and near the bladder, but is operator-dependent; plain radiography does not detect uric acid stones; dual-energy CT distinguishes uric acid stones from calcium-containing stones [10]. In urinary sediment, irregular yellowish-brown plate-like crystals with pH below 6.0 indicate uric acid, and stone analysis by infrared spectroscopy should be performed as soon as possible [10].

In EIAKI, delayed CT (hours to two days after contrast) shows multiple wedge-shaped areas of contrast retention, bilateral in 46 of 50 patients; the Japanese guideline notes that contrast in acute kidney injury requires caution and that diffusion-weighted magnetic resonance imaging shows similar lesions [10, 17]. Renal biopsy shows acute tubular necrosis or minimal changes, with no specific finding [13, 37]. The authors of the review of 40 patients propose that, in the presence of warning signs and raised FEUA, biopsy be avoided and the disease confirmed by genetic testing [37].

5.5. Genetic testing

Genetic testing assigns the type and is indicated mainly when there are complications, serum urate in the mild range with clinical suspicion or a need for family counselling [7, 10]. The Japanese guideline treats variants as a supportive factor and not as a requirement [10]; GeneGuidance summarises that the biochemical phenotype confirms the disease and molecular testing assigns the type [28]. Since both types produce the same biochemistry, both genes must be sequenced [29]. In current practice, next-generation sequencing panels for inherited kidney diseases or exome sequencing are used; the Galician cohort achieved a diagnostic yield of 71% (15 of 21 probands), with three biallelic and 12 monoallelic genotypes [7]. In Ichida's Japanese series (2008), 66 of 71 patients with hypouricaemia had SLC22A12 variants, with a total of 13 variants; W258X accounted for 93 alleles, with 31 homozygotes and 23 compound heterozygotes, and three patients had chronic kidney disease [1]. In populations with known founder alleles, targeted genotyping is useful: in Japan, genotyping of W258X and R90H explains most cases [60], and in the Roma there is a multiplex allele-specific polymerase chain reaction (PCR) method for the two prevalent variants [43]; Mazzierli's review accepts Sanger sequencing as a rapid option when available [37].

The limits of the test should appear in the report and in the interpretation. Sanger sequencing did not identify variants in three of the 40 patients with a clinical picture of RHUC and acute kidney injury (8%) [37]. There are causal intronic variants, such as SLC2A9 c.1419+1G>A, which causes exon 11 skipping [48], and structural rearrangements, such as a 36 kb deletion of SLC2A9 [14] and a large duplication, described in the original article as c.1-2981_1204+16502, detected only by reverse transcription PCR (RT-PCR), semi-quantitative PCR and long-range PCR [53]; these findings require copy-number analysis and, in selected cases, RNA studies. In Galicia, six of 21 probands (29%) had no variant identified, although their biochemistry overlapped with that of monoallelic carriers [7]. A negative result does not exclude the disease, because there are patients with a typical phenotype without variants in the two known genes [10]. Variant classification is difficult: automated tools classify established variants, such as p.Thr467Met, as benign or of uncertain significance, mainly because of the high allele frequency in founder subpopulations, and classification should integrate functional evidence, segregation and clinical data [7]. ClinVar shows conflicting classifications for p.Thr467Met and p.Arg380Trp [42, 46].

The report should state the gene, the transcript and version (NM_144585.4 for SLC22A12; NM_020041.3 for SLC2A9), the HGVS c. and p. description, zygosity, phase (cis/trans) when there are two variants and the ACMG/AMP class (American College of Medical Genetics and Genomics/Association for Molecular Pathology) [5, 7]. Phase requires parental testing: in Jeannin's Pakistani patient, with p.Gly216Arg and p.Arg380Trp, phase was not determined owing to the lack of relatives [31]. Variants of uncertain significance gain weight from biochemical segregation in the family, as in the reclassification of p.Pro268Ser and p.Ser282Leu as likely pathogenic in Galicia [7].

5.6. Practical algorithm

The algorithm of the Japanese guideline starts from a low serum urate [10]. If serum urate is ≤2 mg/dL, the measurement is repeated, because it varies with clinical status, and urinary urate excretion is measured; with increased FEUA or CUA and exclusion of other causes, the diagnosis of RHUC is established. Complications present (EIAKI, stones) are treated and, if there are none, the patient is informed of the risk and of preventive measures. If serum urate is between 2.1 and 3.0 mg/dL, the test is repeated and family history is taken. A near-zero FEUA indicates underproduction and points towards xanthinuria, molybdenum cofactor deficiency or PNP deficiency. Genetic testing of both genes completes the assessment in patients with complications, in cases of mild hypouricaemia with clinical suspicion and in family counselling [7, 10].

5.7. Prenatal and preimplantation diagnosis

The sources consulted do not describe cases of prenatal or preimplantation diagnosis of RHUC, and the guidelines read contain no recommendations on its indication. Counselling on these options follows the general principles for autosomal recessive diseases of usually mild expression (section 8).

6. Differential Diagnosis

6.1. Pathophysiological classification of hypouricaemias

The Japanese guideline divides hypouricaemias into two groups: those due to overexcretion, more frequent, with increased FEUA, and those due to underproduction, with low or near-zero urinary urate excretion [10]. The first group includes RHUC, Fanconi syndrome, Wilson disease, SIADH, malignant tumours, diabetes mellitus, uricosuric drugs (benzbromarone, probenecid), pregnancy and intractable diarrhoea; the second, xanthinuria types I and II, molybdenum cofactor deficiency, PNP deficiency, phosphoribosylpyrophosphate (PRPP) synthetase hypoactivity, idiopathic hypouricaemia due to underproduction, severe liver injury, xanthine oxidase inhibitor drugs (allopurinol) and malnutrition [10]. Drugs excluded, the only causes of isolated asymptomatic hypouricaemia are RHUC and xanthinuria, and the latter is distinguished by near-zero urinary urate excretion [10]. Saudubray adds guanine deaminase deficiency and cytosolic 5′-nucleotidase superactivity, which causes marked hypouricosuria [27].

6.2. Main differential diagnoses

The most important differential diagnosis in asymptomatic hypouricaemia is xanthinuria. A serum urate below 1 mg/dL strongly suggests xanthinuria, but Nyhan's Atlas notes that hypouricaemia also occurs in Fanconi syndrome, with or without cystinosis, in Wilson disease and in the primary defect of tubular urate absorption [62]. The distinction is made from the urine: in xanthinuria urate excretion is near zero and urinary hypoxanthine and xanthine are raised, whereas in RHUC urate excretion is normal or high [10, 25]. Xanthinuria is much less frequent, with a few hundred patients described [10].

Secondary hypouricaemias are distinguished by context. SIADH and diabetes are generally associated with serum urate above 2.0 mg/dL and with hyponatraemia or hyperglycaemia; Wilson disease and Fanconi syndrome have other abnormalities (low caeruloplasmin; aminoaciduria and hypophosphataemia); hypouricaemias due to drugs or tumours are recognised by their course [10]. In a study of 3,258 outpatients, eight of 13 with hypouricaemia had transient hypouricaemia due to diabetes, cirrhosis, hepatocellular carcinoma, allopurinol or benzbromarone [10]. Hypouricaemia is constant in cystinosis [63] and is part of the tubulopathy of Wilson disease [62]. Hypouricaemia with high FEUA also occurs in hypervolaemic states [31].

In acute kidney injury after exercise, the main differential diagnosis is rhabdomyolysis, with markedly raised CK, myoglobinuria and dark urine; EIAKI associated with hypouricaemia has normal or slightly raised CK and severe loin pain [10]. Jeannin and colleagues list the factors that favour hypovolaemia or exertional rhabdomyolysis and should be sought: thyroid disorders, decompensated diabetes, hypocortisolism, hypokalaemia, environmental conditions (altitude, humidity, heat), exercise intensity, drugs and toxins (alcohol, stimulants, supplements, anticholinergics, statins), infections and genetic muscle diseases (glycogen storage diseases, fatty acid oxidation defects, mitochondrial diseases, sickle cell disease, muscular dystrophies) [31]. ALPE also occurs in people without hypouricaemia: in Ishikawa's series, only about half of the patients with known serum urate had RHUC [17].

In hereditary diseases with uric acid urolithiasis, the direction of serum urate is the main discriminator: partial HPRT deficiency and PRPS1 superactivity cause hyperuricaemia with hyperuricosuria, and ADTKD due to UMOD hyperuricaemia with hypouricosuria [25]. Adenine phosphoribosyltransferase deficiency forms radiolucent 2,8-dihydroxyadenine stones with normal serum urate [25]. The genetic approach to nephropathies and urolithiasis of undetermined cause in adults includes RHUC among the causes to be sought on a panel.

7. Treatments and Risk Management Strategies

7.1. General principles

There is no treatment that corrects the transport defect and no drug approved for renal hypouricaemia; low serum urate itself is not treated, and management is preventive and directed at complications [10, 29]. The Japanese guideline recommends that, once the diagnosis is made, the person without complications be informed of the risk of EIAKI and urolithiasis and advised to take preventive measures, and that any complications present be treated [10]. The Orphanet summary, reviewed by ERKNet, follows the same line: complications are treated as in the general population, and asymptomatic patients should be considered at high risk and adopt prophylactic measures, such as increased fluid intake and urinary alkalinisation [2].

7.2. Treatment of exercise-induced acute kidney injury

EIAKI is treated as ordinary acute kidney injury [10]. Reports describe rehydration, calcium channel blockers and dopamine to improve renal flow, and haemodialysis when there is oliguria, uraemia, electrolyte disturbance or heart failure [10]; in Ishikawa's review, 34 of 116 patients required short-term dialysis [10], and in Mazzierli's review 22.5% [37]. The authors of the latter propose an expectant approach with supportive therapy and monitoring for complications, given the spontaneous recovery of most patients, and confirmation by genetic testing instead of biopsy [37]. NSAIDs should be stopped [10]. In PRES, haemodialysis and blood pressure control with intravenous nicardipine were used with recovery [55]. The use of corticosteroids in cases interpreted as interstitial nephritis, described in isolated reports [54], has no basis in the pathophysiology of EIAKI.

7.3. Prevention of acute kidney injury: non-pharmacological measures

The Japanese guideline, with a consensus level of 4 out of 5, lists as preventive measures abundant water intake before exercise, avoidance of exercise while taking NSAIDs or of NSAIDs themselves, and avoidance of strenuous exercise [10]. Limitation of intense anaerobic exercise is presented as the most effective measure [29, 38]. Counselling should be individual and realistic: the fighter who wrote the appendix to the guideline asks sports physicians to give information on the appropriate type and intensity of exercise, that analgesics and cold remedies with less renal impact be chosen and that post-exertional loin pain not be dismissed as muscle pain, and concludes that, knowing about the disease, patients can practise sport, including marathons and martial arts [10]. Dehydration and rapid weight loss before competitions are triggers to be avoided [10, 37]. Episodes after moderate exercise show that no intensity threshold guarantees protection [54].

7.4. Prevention of acute kidney injury: xanthine oxidoreductase inhibitors

The use of xanthine oxidoreductase (XOR) inhibitors rests on two hypotheses: reducing urate production during and after exercise, and with it the filtered load, and reducing oxygen radical production by xanthine oxidase [10, 11]. The human evidence is limited to case reports. Yeun and Hasbargen treated a 29-year-old Pakistani man with recurrent EIAKI with allopurinol 300 mg/day for five days before repeating the exercise test: the patient had no kidney injury and urate excretion did not increase (0.28 to 0.22 mg/min), unlike what had happened without treatment [35]. A 400-metre sprinter in the United States did not have a recurrence after taking allopurinol 300 mg/day for the three days before races, according to the description in the Japanese guideline and in the review by Hakoda [10, 11, 66]. A 16-year-old Japanese footballer, compound heterozygous for URAT1 variants, with two stage 3 EIAKI episodes despite hydration and NSAID avoidance, started febuxostat 20 mg/day, increased to 40 mg/day, and had no recurrence during 16 months of intense training, without adverse effects; FEUA did not change with the drug [38]. In the murine model, allopurinol and topiroxostat prevented the injury [36].

The Japanese guideline formulated clinical question 2 and concluded that no firm rule can be established: XOR inhibitors may prevent the onset or recurrence of EIAKI, and their administration should be decided by weighing benefits and harms, particularly in athletes and in patients with previous EIAKI [10]. The guideline does not recommend treating all patients, because not all have EIAKI and the drugs have adverse effects, and notes that there are no studies in Asians, no randomised trials or studies with several patients, and no data defining dose or duration [10]. Orphanet records little consensus [2]. The authors of the febuxostat case propose the indication in patients with repeated EIAKI despite conventional prophylaxis who wish to continue anaerobic exercise [38]. In all cases, the use is off-label.

The doses used in the reports (allopurinol 300 mg/day for three to five days before exertion; febuxostat 40 mg/day continuously) have not been validated in RHUC and should be compared with those of the labels. In the United States Food and Drug Administration (FDA) label, allopurinol is indicated in gout, in hyperuricaemia associated with cancer therapy and in recurrent calcium oxalate stones with uricosuria above 800 mg/day in men or 750 mg/day in women, at 200–300 mg/day for the latter indication, and in gout it is started at 100 mg/day, with weekly increments of 100 mg up to a maximum of 800 mg/day and a starting dose of 50 mg/day in renal impairment [67]. The Portuguese summary of product characteristics (SmPC) of Zyloric® provides for 100 to 800 mg/day in adults (2–10 mg/kg/day) and, under 15 years, 10–20 mg/kg/day up to a maximum of 400 mg/day [68]. The European urolithiasis guideline indicates 100–300 mg/day in adults (100 mg in isolated hyperuricosuria) and 1–3 mg/kg/day in children, with adjustment in renal impairment and contraindication in pregnancy and breastfeeding [61]. Allopurinol is associated with severe hypersensitivity reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms) in carriers of the HLA-B*58:01 allele, whose frequency reaches up to 20% in Han Chinese, 8–15% in Thai and about 12% in Koreans, and is 1–2% in Japanese and Europeans; the SmPC advises considering genotyping before starting [67, 68]. Allopurinol interacts with mercaptopurine and azathioprine, whose dose should be reduced [67].

Febuxostat is approved only for chronic hyperuricaemia of gout in adults. In the United States (Uloric®), it is reserved for patients with an inadequate response, intolerance or contraindication to allopurinol, at a dose of 40 or 80 mg/day, with a boxed warning of increased cardiovascular mortality in patients with established cardiovascular disease (CARES trial) [69]. In the European Union (Adenuric®), the dose is 80 mg/day, which may be increased to 120 mg/day, without restriction to second line; safety and efficacy under 18 years have not been established, and it should not be used in pregnancy or breastfeeding [70]. The authors of the febuxostat case discuss cardiovascular safety and consider the risk low in an adolescent, but acknowledge that safety in RHUC is unknown [38]. Topiroxostat is available only in Japan [10].

7.5. Prevention and treatment of urolithiasis

Treatment of stones already formed is the same as for other urolithiasis: spontaneous passage when possible and removal by extracorporeal shock wave lithotripsy, percutaneous nephrolithotomy or ureterorenoscopy when there is persistent pain, infection or loss of renal function [10]. Dissolution of uric acid stones by urinary alkalinisation is also effective in RHUC, although slow [10]. Prevention rests on three measures of the Japanese guideline, all with a consensus level of 4 out of 5: fluid intake ensuring urine output of at least 2,000 mL/day, with water as the preferred drink instead of alcohol or sugary or purine-rich drinks; alkalinisation with potassium and sodium citrates, with urinary pH between 6.0 and 7.0, because pH ≥7.5 favours precipitation of calcium phosphate and sodium urate; and a diet with vegetables and seaweed, avoiding large amounts of purine-rich foods, without strict restriction, which has little benefit [10]. The solubility of uric acid is 15 mg/dL at pH 5.0 and 200 mg/dL at pH 7.0, and an association between RHUC and acidic urine has been described [10]. The guideline accepts combining alkalinising agents and XOR inhibitors when urinary urate excretion is increased, although few studies have evaluated this in RHUC [10]. A Japanese patient with a renal stone and CKD had improvement of stone-related urinary abnormalities on potassium citrate [59].

Citrate doses have not been defined specifically for RHUC and are extrapolated from uric acid urolithiasis. The European urolithiasis guideline recommends alkaline citrates in uric acid stone formers (strong recommendation; level of evidence 3), at a dose of 3.25–9.75 g/day (10–30 mmol/day) in adults, adjusted to urinary pH, and 0.1–0.15 g/kg/day in children, with fluid intake of 2.5–3.0 L/day, urine output of 2.0–2.5 L/day and urine specific gravity below 1,010 [61]. The French PNDS for paediatric urolithiasis recommends hyperhydration of 2–3 L/m²/day spread throughout the day, urine specific gravity below 1,010 or osmolarity below 300 mOsm/L in the first morning urine, and alkalinisation with a target pH of 6.5–7 for uric acid stones, preferably with potassium citrate 150 mg/kg/day (or potassium bicarbonate) in three to four doses, adapted to renal function and digestive tolerance, with monitoring of serum potassium [26]. The target pH differs slightly between sources (6.0–7.0 in the Japanese guideline and the US label; 6.5–7 in the PNDS; 6.2–6.8 in the Uralyt-U® SmPC), and the Japanese guideline is the reference in RHUC [10, 26, 71].

The US potassium citrate label includes strenuous exercise in unconditioned individuals among the conditions that predispose to hyperkalaemia [72], which is relevant to patients with RHUC who undertake intense exertion; the sources consulted do not describe complications of this type in patients with RHUC. Patients with ongoing EIAKI or renal failure should not start potassium citrate, which is contraindicated in acute renal failure and with markedly reduced GFR [71, 73].

7.6. Agents to avoid and precautions

Uricosuric drugs (benzbromarone, probenecid, lesinurad, verinurad, dotinurad) act on URAT1 itself and are not a therapy for RHUC; in biallelic patients urate excretion no longer responds to these drugs, and those with a potent effect reproduce the tubular urate load associated with kidney injury [11, 28, 33]. Saudubray contraindicates lesinurad and probenecid in diseases with urinary urate overload, because they worsen precipitation [25]. NSAIDs should be avoided, especially before or after exertion, because anti-inflammatory use is frequent in EIAKI episodes [10]. The Japanese guideline draws attention to caution with iodinated contrast in acute kidney injury, when delayed CT is being considered [10]. Dehydration, including that associated with rapid weight loss for competitions, is a trigger to be avoided [10].

7.7. Special populations

In childhood and adolescence, EIAKI clusters from the age of 11 years and in school sport [10, 13]. Paediatric citrate doses derive from the PNDS and the European urolithiasis guideline (section 7.5) [26, 61]; allopurinol has a paediatric dose in the Portuguese SmPC (10–20 mg/kg/day, maximum 400 mg/day) and in the European guideline (1–3 mg/kg/day in urolithiasis), but has no indication in RHUC [61, 68], and febuxostat has no established safety under 18 years [69, 70]. The Japanese guideline includes pregnancy among the causes of hypouricaemia due to overexcretion [10]; the sources consulted do not describe the course of RHUC in pregnancy. Allopurinol should only be used in pregnancy when there is no safer alternative and is not recommended during breastfeeding; febuxostat should not be used in either situation; potassium citrate should only be given in pregnancy and lactation when strictly necessary [68, 70, 73].

In kidney transplantation, RHUC can be transferred with the donor kidney. An Indian donor compound heterozygous for SLC2A9 variants donated a kidney to her son, who after transplantation maintained serum urate of 0.6 mg/dL and FEUA of 38%, with normal renal function in donor and recipient at three months; the authors gathered three earlier reports with Japanese donors carrying SLC22A12 variants, none with EIAKI or urolithiasis in the recipient [45]. In a father-to-son transplant, both heterozygous for a URAT1 nonsense variant, protocol biopsy at three months showed uric acid crystals and calcium microcalculi in the distal tubules, with serum urate falling from 5.2 to 1.9 mg/dL three days after transplantation and FEUA of 29%; the changes disappeared within one year without an XOR inhibitor [11]. The authors recommend informing recipients of affected donors and advising avoidance of strenuous exertion and dehydration [45].

In the transition to adulthood, the period of greatest risk coincides with competitive sport in adolescence and early adulthood (median age of EIAKI 17–19 years), which justifies reviewing counselling at this stage [10, 13]. The sources consulted do not describe specific perioperative recommendations, beyond the general ones of hydration and avoidance of nephrotoxins.

7.8. Comparative regulatory status

The sources consulted did not identify any drug with orphan designation, marketing application or specific authorisation for renal hypouricaemia; the Orphanet page associates four orphan designations or orphan medicinal products with the code, whose list could not be consulted [2]. The situation in Brazil (registration and package insert at ANVISA) was not verified.

7.9. Available evidence

The data do not allow efficacy to be estimated. They are open, uncontrolled case reports, each with a single patient, and an animal model; there are no randomised trials, no studies in Asians with several individuals and no data on dose and duration [10]. Absence of recurrence in one patient may reflect natural variability, because recurrence occurs in about 20% to 24% of untreated patients [10, 13]. The review by Hakoda and Ichida mentions a randomised trial in which allopurinol 300 mg prevented stone recurrence in patients with hyperuricosuria, but without RHUC [11]. For urolithiasis, citrate is based on the evidence for uric acid urolithiasis in general (level 3 in the European guideline) [61].

7.10. Developments in the last 12 months and research

Publications from the last 12 months are observational. The Galician cohort (2026) described, in a European population, that monoallelic carriers of SLC22A12 and SLC2A9 variants frequently have mild hypouricaemia, added three variants to the spectrum and proposed investigating FEUA when serum urate is persistently below about 3 mg/dL [7]. The Shizuoka study (December 2025) associated hypouricaemia with rapid decline in GFR, without an increase in cardiovascular events or mortality [57]. A new homozygous SLC2A9 variant (p.Asn333Lys) was described in a Chilean family, in which only the physically active brother had EIAKI, while the homozygous sister, inactive because of hip dysplasia, remained asymptomatic [74], as was the combination of URAT1 variants p.Ala209Val and p.Phe379Leu in a patient with CKD and urolithiasis treated with potassium citrate [59]. ClinicalTrials.gov lists no interventional trials directed at RHUC; the National Institutes of Health (NIH) Clinical Center has been recruiting since December 2023 for a prospective natural history study of disorders of purine and pyrimidine metabolism that includes SLC2A9 and SLC22A12 [75], and the UK rare kidney disease registry RaDaR includes hereditary renal hypouricaemia [76]. The sources consulted do not describe gene therapy, gene editing or drugs in development for RHUC; pharmacological research on URAT1 is directed the opposite way, towards uricosurics for gout [11].

7.11. Guideline recommendations and divergences

The Japanese guideline is the only specific guideline and serves as the reference [10]. Recommendation 1 (strong) is to investigate any serum urate ≤2.0 mg/dL; recommendation 2 leaves the decision on XOR inhibitors to individual weighing of benefit and risk [10]. The Orphanet/ERKNet summary adds prophylactic urinary alkalinisation in asymptomatic individuals [2], which the Japanese guideline recommends mainly in patients with stones [10]. The European urolithiasis guideline and the French PNDS do not address RHUC as an entity, but define the citrate doses and urine output targets used by extrapolation, with a slightly different target pH [26, 61]. Thresholds for suspicion diverge: the Japanese guideline uses 2.0 mg/dL with repetition in the 2.1–3.0 mg/dL range [10], the Japanese genetic study suggests 3.0 mg/dL in men [60] and the Galician cohort about 3 mg/dL persistently [7].

8. Reproductive Options and Family Counselling

8.1. Inheritance patterns and recurrence risks

RHUC1 is transmitted in an autosomal recessive manner in the clinical sense: complications cluster in homozygotes and compound heterozygotes, and the parents of a patient are, as a rule, carriers [1, 37]. With two heterozygous parents, each child has a 25% probability of inheriting two affected alleles, 50% of being a carrier and 25% of inheriting neither, in accordance with recessive Mendelian inheritance. Carriers are not, however, biochemically neutral: many have mild hypouricaemia and slightly increased FEUA, which amounts to an allele dosage effect or codominant expression [7, 8]. In RHUC2, OMIM records recessive and dominant inheritance, and heterozygotes for some variants, such as p.Thr125Met, p.Arg380Trp and p.Arg198Cys, have overt hypouricaemia, sometimes below 2 mg/dL [3, 9, 19]. A heterozygote with mild RHUC2 therefore has a 50% probability of transmitting the variant to each child, with variable biochemical expression [9]. Pezantes' Chilean family illustrates the recessive inheritance of severe RHUC2: normouricaemic, non-consanguineous heterozygous parents, two homozygous children with hypouricaemia and one daughter homozygous for the reference allele [74].

8.2. Family studies

Once a case has been identified, testing siblings is useful, because they have a 25% probability of sharing the genotype and benefit from the same counselling on exercise and hydration. Family screening begins with serum urate and FEUA, and targeted genetic testing confirms the genotype and the phase of the variants [7, 10]. In the consanguineous Roma family of the Spanish series, the proband's two siblings had serum urate of 1.20 and 1.00 mg/dL and FEUA of 23% and 54%, without symptoms, while the mother had recurrent urolithiasis [9]. In Galicia, testing of 12 relatives from four families identified seven monoallelic carriers, several with mild hypouricaemia, and five non-carriers, all with normal serum urate [7]. Segregation analysis also helps to reclassify variants of uncertain significance [7].

8.3. Populations with founder variants

In populations with frequent founder alleles, the probability that a partner is a carrier is high. In Japan, the combined frequency of non-functional URAT1 alleles approaches 3% and heterozygosity reaches about 6% of the population [11]. In the Roma, the sum of the frequencies of p.Thr467Met (5.56%) and the deletion (1.92%) is about 7.5%, and heterozygosity is probably double that in Japan [11, 12]; endogamy favours homozygosity, as shown by the deviation from Hardy-Weinberg equilibrium for the deletion in Czech and Spanish cohorts [12]. In these settings, the authors recommend routinely considering RHUC1 in the assessment of Roma patients with hypouricaemia and hyperuricosuria [12, 43].

8.4. Prenatal and preimplantation diagnosis and minors

The sources consulted do not describe the use of prenatal diagnosis or preimplantation genetic testing in RHUC, and the guidelines read do not discuss them. Since this is a disease of usually mild expression, preventable and without effect on life expectancy [2], these options are not part of described practice. Testing of minors has a direct benefit when it allows guidance on sports practice in adolescence, which is the period of greatest risk of EIAKI [10, 13]; measurement of serum urate and FEUA in the siblings of a patient is a non-invasive first step, with the caveat that physiological serum urate is low in the first months of life [12].

8.5. Content of counselling

Counselling includes an explanation of the mechanism and of the usually benign nature of the disease; the risk of EIAKI and urolithiasis, higher in biallelic genotypes and in men [10, 37]; preventive measures (hydration before and after exertion, avoidance of NSAIDs and of strenuous anaerobic exercise, abundant urine output) [10]; the need to inform physicians who may treat an acute kidney injury, to avoid unnecessary biopsies [37]; the meaning of a negative genetic result; and, where applicable, the assessment of relatives as kidney donors [45].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Most data come from Japan and measure the frequency of low serum urate in health screening, which is an indirect marker of RHUC. The Japanese guideline estimates prevalence at about 0.2% in men and 0.4% in women, based on a study of 90,170 men and 136,935 women aged 40 to 74 years from 24 prefectures, in which serum urate ≤2.0 mg/dL was observed in 193 men (0.21%) and 540 women (0.39%) [10]. Other Japanese studies gave 0.14% in men and 0.40% in women among 21,147 workers, 0.09–0.12% and 0.36–0.51% in about 10,000 participants per year over four years and 0.18% in 21,260 military personnel [10]. In the J-MICC cohort of 4,993 participants, hypouricaemia was 0.118% in men and 0.376% in women, with probable genetic confirmation in nine of the ten cases [60]; in a larger set from the same cohort, with 30,685 participants, it was 0.18% in men and 0.54% in women [8]. OMIM cites a hypouricaemia frequency of 0.94% in a large Japanese database studied by Matsuo (2008), without stating in the entry the threshold used [3]. The prevalence of serum urate ≤1.0 mg/dL, which almost always corresponds to two non-functional URAT1 alleles, is about 0.1% in both sexes, close to the 0.09% expected from the square of the allele frequency of 3% [11].

In Korea, in the KoGES study of 172,970 adults aged 40 to 79 years, hypouricaemia was 4.16 per 1,000 (1.10 in men and 5.75 in women), highest in women aged 40 to 49 years [77]; in two other Korean cohorts, W258X and R90H accounted for 90% of cases [50]. Outside East Asia, data are scarce: in a retrospective survey of serum urate in 47,420 patients, followed by selective studies, Harkness and colleagues identified only two women with marked persistent hypouricaemia and high urinary urate, with no case of xanthine oxidase deficiency [1]; among 3,200 German blood donors studied from 1962, only three women had serum urate ≤2.0 mg/dL [11]. Orphanet classifies the prevalence as unknown [2]. These figures measure hypouricaemia in screening populations, not confirmed diagnoses, and their application to other populations is not valid.

9.2. Geography, ancestry and founder effect

In Japan and Korea, the high frequency results from W258X, with an allele frequency of 2.25% to 2.37% in general population samples, and from R90H, with 0.28% to 0.40% [11, 60, 78]. In Europe, the Roma population has the highest frequencies described: among 1,016 randomly selected Roma from five regions of Slovakia, the Czech Republic and Spain, p.Thr467Met had a frequency of 5.56% and the deletion 1.92%; among 109 Roma from North Macedonia, p.Thr467Met reached 6.4% and the deletion was absent [12]. The Roma, numbering about 8 to 11 million people in Europe, descend from a group of about 1,000 individuals who left India about 1,000 years ago and are concentrated in Central and South-Eastern Europe and the Iberian Peninsula [9, 12]. The Slovak authors relate this frequency to lower mean serum urate in the Roma of Eastern Slovakia (226.5 versus 259.1 µmol/L) and to a higher risk of end-stage CKD in this population, without proof of a causal relationship [12].

In Spain, the RenalTube group series gathered 31 families: those of Roma origin had RHUC1 due to p.Thr467Met and the deletion, and those of non-Roma origin had mainly RHUC2 due to the founder variant SLC2A9 p.Thr125Met, present in 13 families (about 42%) and responsible for up to 93% of families with RHUC2 [9, 58]. In Galicia, in the north-west of the Iberian Peninsula, the NephroGalGen cohort identified 15 probands with variants in ten distinct variants, among them p.Thr467Met, p.Val138Leu and SLC2A9 p.Thr125Met, and 58 additional unsuspected carriers [7]. In Israel, RHUC1 in Jews of Iraqi origin is due to the probable founder variant p.Arg406Cys [32]; as early as 1989 Gafter and colleagues had noted that, of 11 families with a presecretory defect, eight were of Sephardi Jewish origin and six of these Iraqi, and Greene's American patient was also of Iraqi origin [1]. RHUC2 has been described in Arab families, in an Ashkenazi man homozygous for a 36 kb deletion and in an 84-year-old Sephardi man homozygous for p.Thr125Met [6, 14, 15]. In Greece, a 30-year-old man from Crete, with no family history, had recurrent EIAKI due to a homozygous deletion of exons 8 to 12 of SLC2A9, and in the Czech Republic two siblings of unrelated parents were homozygous for a single-nucleotide insertion; the sister presented at the age of 13 with abdominal pain and the brother had urolithiasis [3, 6]. There are reports from Italy, the United Kingdom, the Czech Republic, Greece, the United States, Chile, China, India and Pakistan [31, 35, 37, 39, 45, 47, 49, 52, 74]. In China, screening of 31 hypouricaemic individuals from the general population found URAT1 variants in four and GLUT9 variants in two, without W258X or R90H [11], and a series of 19 patients suggests that SLC2A9 p.Trp315Ter may be recurrent [49].

The sources consulted do not include population data from the United States or from Portugal or Brazil. Mazzierli's review shows that 93% of published patients with acute kidney injury were of Asian ancestry [37], which also reflects the distribution of research. The absence of data does not demonstrate low frequency: Orphanet considers the disease probably underdiagnosed, with increasing reports in Europe and North America [2], and the Galician cohort found carriers among individuals tested for other reasons [7].

9.3. Special populations

Women have more frequent hypouricaemia, owing to the effect of sex hormones on urate excretion, but men have almost all EIAKI episodes (202:18) [10, 11]. Athletes and those practising sports with sprints, combat sports or sports with rapid weight loss are the group at highest risk of EIAKI [10, 38]. Kidney donor candidates with hypouricaemia should be investigated before donation [45].

9.4. Reference networks, registries and patient organisations

The relevant European reference network is ERKNet, the network for rare kidney diseases, which reviewed the Orphanet summary [2, 16]. The French ORKiD network drew up the PNDS for paediatric urolithiasis, which includes the disease [26]. In the United Kingdom, the RaDaR registry includes hereditary renal hypouricaemia [76], and in the United States the NIH natural history study recruits patients with SLC2A9 and SLC22A12 variants [75]. Orphanet lists expert centres, diagnostic tests and patient organisations associated with code ORPHA:94088 [2]; the sources consulted do not identify a patient organisation specific to RHUC.

10. Illustrative Clinical Case

Mazzierli and colleagues, from Florence and Prato, Italy, described a 17-year-old boy of Asian ancestry, with no relevant personal or family history, admitted to the emergency department with vomiting, fever and bilateral flank pain of four days' duration, which began after playing basketball [37]. Blood pressure and vital signs were normal. Tests showed creatinine of 8.49 mg/dL (estimated GFR of 8 mL/min/1.73 m² by the revised Schwartz formula), urea of 90 mg/dL, normal electrolytes and acid–base balance, CK of 315 IU/L (normal 50–230), myoglobin of 63 µg/mL and serum urate of 4.6 mg/dL, within the reference range (3.7–7.0); the urine showed mild microscopic haematuria, tubular proteinuria of 346.8 mg/24 h and pH of 6.0, with urinary uric acid of 996 mg/L and a calculated undissociated uric acid concentration of 80 mg/L, below the solubility limit [37]. Immunological and infectious screening was negative, and ultrasound showed normal-sized kidneys with slightly increased cortical echogenicity, without obstruction, stones or nephrocalcinosis [37].

The kidney injury persisted despite intensive hydration and a renal biopsy was performed, which showed acute tubular necrosis with interstitial oedema, denudation and atrophy of the tubular basement membrane, proximal tubular cells detached into the lumen and coagulative necrosis of the epithelium, with normal glomeruli and vessels and immunofluorescence negative for C3, C4, immunoglobulins and fibrinogen (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10089983/figure/Fig1/) [37]. With supportive therapy, renal function recovered fully 14 days after onset. As estimated GFR rose, serum urate fell, becoming undetectable ten days after admission; at that point, FEUA was 133% (local reference 4–8%), which suggested renal hypouricaemia (Figure 2 of the article, with the course of estimated GFR and serum urate: https://pmc.ncbi.nlm.nih.gov/articles/PMC10089983/figure/Fig2/) [37]. Massively parallel sequencing, with an exome-based virtual panel of genes for inherited kidney diseases, identified a novel homozygous missense variant, classified as pathogenic (class 5), in SLC2A9, described as c.[361G>A], which confirmed RHUC2 [37]. The patient was discharged without sequelae; over the following three years, renal function remained normal and serum urate persistently undetectable [37].

The case brings together the elements that the same authors' review identified as warning signs: male sex, adolescence, Asian ancestry, prodromes after exertion, markedly raised creatinine with moderate urea, normal electrolytes, mild urinary abnormalities and normal serum urate in the acute phase with markedly raised FEUA [37]. It also shows that normal serum urate during acute injury can delay diagnosis and that the biopsy, which was non-specific, could have been avoided if FEUA had been measured on admission [37]. A FEUA above 100% and undetectable serum urate are consistent with the biallelic form of SLC2A9 [14, 31]. The article describes the variant only by the c. change, without stating the transcript or the protein consequence, so the sources consulted do not allow its normalisation on the MANE transcript.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

RHUC is not lethal and most carriers have no symptoms throughout life; affected individuals do, however, have a higher risk of renal complications than the general population [2, 10]. The short-term prognosis of EIAKI is good: episodes last on average about two weeks, recovery is complete in about 77.5% with supportive therapy and there are no reports of progression to chronic dialysis [10, 37]. Recurrence affects 19.5% to 24.1% of patients in the large Japanese series and 60% of patients with described follow-up in the review of published cases [10, 13, 37]. The frequency of EIAKI in people with RHUC varies with the mode of selection: 6.5% (2 of 31) when those diagnosed because of EIAKI itself are excluded, 6.1% (11 of 179) in a national survey and 21.1% to 24.1% in hospital series that include them [10, 34]. The frequency of urolithiasis lies between 6.1% and 12.5% in the Japanese series and reached 30.8% in a small series with prolonged follow-up [10, 33, 34].

The long-term effect on renal function is uncertain. In a large Japanese population study, hypouricaemia was associated with rapid decline in GFR (odds ratio 1.59), without an effect on cardiovascular events or mortality [57], whereas in a small study of patients with genetic confirmation there was no decline in GFR over four years [34]. Mazzierli's review accepts that repeated episodes of acute kidney injury may lead to CKD [37]. These data come from Japanese populations and small series, and there are no studies of treated natural history.

11.2. Surveillance

The sources consulted do not define a specific surveillance schedule for RHUC. The following table gathers the existing recommendations, with their source, and indicates when the interval is not defined.

12. Summary and Final Considerations

Hereditary renal hypouricaemia results from loss of proximal urate reabsorption due to variants of SLC22A12 (URAT1, type 1) or SLC2A9 (GLUT9, type 2) [10]. The diagnosis is biochemical: persistent serum urate ≤2.0 mg/dL, increased FEUA and exclusion of other causes, according to the Japanese guideline, with genetic testing of both genes to assign the type [10]. Monoallelic carriers frequently have mild hypouricaemia between 2 and 3.3 mg/dL, and some authors propose investigating serum urate persistently below about 3 mg/dL [7, 60]. RHUC2 tends to be biochemically more severe, with FEUA above 100% in homozygotes [10, 14].

The geographical distribution is marked by founder variants: W258X and R90H in Japan and Korea, p.Thr467Met and the in-frame deletion in European Roma, SLC2A9 p.Thr125Met in Spain and p.Arg406Cys in Jews of Iraqi origin [9, 11, 12, 32]. The prevalence of serum urate ≤2.0 mg/dL is around 0.2% in men and 0.4% in women in Japan; in other populations, including European populations other than the Roma, prevalence has not been established [2, 10].

Most affected people have no symptoms. The relevant complications are acute kidney injury induced by anaerobic exercise, typical of adolescent boys and young adult men, with loin pain, nausea, vomiting, markedly raised creatinine, slightly raised CK and paradoxically normal serum urate in the acute phase, and uric acid or calcium oxalate urolithiasis [10, 37]. FEUA measured during or after the episode allows the diagnosis and avoids biopsies [37]. Prevention rests on hydration, avoidance of NSAIDs and of strenuous anaerobic exercise and, for urolithiasis, a urine output of at least 2 L/day with citrate and urinary pH of 6.0 to 7.0 [10]. Xanthine oxidoreductase inhibitors may be considered in athletes and in patients with repeated EIAKI, off-label, on the basis of isolated cases and animal models [10, 36, 38]. The long-term effect on renal function remains under study [34, 57].

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