Hereditary renal hypouricemia (ORPHA:94088)
A genetic renal tubular disorder characterized by urinary urate wasting that typically leads to asymptomatic hypouricemia and predisposes to urolithiasis and exercise-induced acute renal failure (EIARF).
Epidemiology
Whilst the prevalence is not known in Europe, hereditary renal hypouricemia (RHUC) is reported as common in Japan and South Korea. RHUC is likely underdiagnosed as patients are typically asymptomatic; however, there are increasing reports for European countries and North America.
Clinical description
RHUC may be silent and sometimes the diagnosis is incidental; thus, clinical presentation may be at any age. However, chronic urinary urate wasting predisposes to several complications, such as nephrolithiasis, hematuria, pyelonephrithisis and nephrocalcinosis. In additions, several reports indicate that this disorder increases the risk of EIARF.
Etiology
The disorder is the result of impaired urate reabsorption along the proximal tubule, leading to increased urinary urate excretion and secondary hypouricemia. Two genetic loci have been associates with the disorder: SLC22A12 (11q13.1), encoding the urate transporter 1 (URAT1), and SLC2A9 (4p16.1), encoding for the urate transporter called glucose transporter 9 (GLUT9).
Diagnostic methods
Diagnosis is typically suspected on the incidental finding of low serum uric acid levels (SUA). According to the current clinical practice guideline, diagnosis is confirmed by the presence of the following findings : (1) SUA lower than 2 mg/dl in two consecutive blood examinations, (2) high urinary fractional excretion of urate (greater than 10%) and/or uric acid clearance, (3) in the absence of other causes of hypo-uricemia. Identification of the causative genes, a history of excercise-induced acute kidney injury (EIAKI) or a family history of RHUC is supportive of diagnosis.
Differential diagnosis
The differential diagnosis includes several conditions resulting in (1) increased excretion and (2) reduced uric acid production. The first group of disorders includes Fanconi syndrome, Wilson's disease, syndrome of inappropriate secretion of vasopressin (SIADH), neoplasia, some drugs (as probenecid), diabetes mellitus. The second one includes some rare inherited disorders affecting purine metabolism, as xanthinuria types 1 and 2 and purine nucleoside phosphorylase deficiency (PNP deficiency). In addition, severe liver diseases, malnutrition, some medications (allopurinol) and molybdenum cofactor deficiency may cause urate underproduction.
Genetic counseling
The disorder has both an autosomal recessive and autosomal dominant pattern of inheritance. Biallelic loss-of-function mutations of SLC22A12 and either homozygote and heterozygote SLC2A9 mutations have been described in RHUC patients.
Management and treatment
Complications of RHUC, such as nephrolithiasis and EIAKI, should be treated as in the general population. Asymptomatic patients should be considered at high risk to develop these complications, thus prophylactic measures, such as increased fluid intake and urine alkalization, should be undertaken. There is little consensus on the use of xanthine oxidoreductase inhibitors (XOR) to protect from EIAKI. The rationale to use this medication is to counteract the increased uric acid (UA) production during exercise, reducing the filtered load and lowering the risk of UA precipitation in the tubules. Some reports suggest that XOR might protect from EIAKI onset and/or recurrence, but further studies are required.
Prognosis
RHUC is not lethal and may be asymptomatic. Affected individuals have a higher risk to develop renal complications (renal stones, EIAKI) compared with the general population.

                            Last update: 
                            May 2020


                            - Expert reviewer(s): 
                            Pr Miriam ZACCHIA | ERKNet*


                                * European Reference Network