Hypouricemia caused by a renal tubular defect has been termed “renal hypouricemia”, and loss-of-function mutations of the SLC22A12 and SLC2A9 genes are called type 1 and type 2 renal hypouricemia, respectively ^[1][48]. The SLC22A12 and SLC2A9 genes encode the apically located URAT1 and the basolaterally located GLUT9, respectively, the main reabsorptive uric acid transporters in the proximal tubule. In renal hypouricemia type 1 or 2, the fractional excretion of uric acid increases to much higher than 10% despite a very low level of serum uric acid. Patients with renal hypouricemia can present with hematuria, urolithiasis, and exercise-induced AKI.

Among different mutations in the SLC22A12 gene, W258X (rs121907892) was predominant in patients with type 1 renal hypouricemia in reports from Japan ^[2][49] and Korea ^[3][50]. While type 1 renal hypouricemia mainly occurs in Asian children, cases of type 2 renal hypouricemia were reported in various parts of the world, including Asia, the Middle East, and Europe. Patients with type 2 renal hypouricemia were often diagnosed during adulthood ^[4][51].

Exercise-induced AKI is an important clinical presentation of renal hypouricemia. It can be differentiated from rhabdomyolysis-associated AKI because of the absence of elevated creatinine kinase levels and myoglobinuria. Urine data are compatible with pre-renal azotemia, and kidney function gradually improves with hydration. The characteristic computed tomography findings are patchy renal vasoconstriction or multiple patchy wedge-shaped delayed-contrast enhancements in the kidneys ^[5][52]. The reason why exercise-induced AKI can occur in patients with renal hypouricemia is unclear. Two different aspects were viewed in the pathogenesis of renal injuries: a low serum uric acid level and a high urine uric acid level. Interestingly, uric acid may function as an antioxidant in plasma and can act as a pro-oxidant within the cell ^[6][53]. In patients with hypouricemia, the antioxidant activity of uric acid is overwhelmed by the massive concentration of reactive oxygen species produced by exhaustive exercise. Thus, the loss of antioxidant activity in plasma may lead to vascular constriction and endothelial damage, progressing to AKI ^[7][54]. According to the other viewpoint, in the kidneys of renal hypouricemia after strenuous exercise, intense inflammation might be stimulated by a high intraluminal concentration of uric acid in the proximal straight tubule and the thick ascending limb of Henle’s loop ^[8][55]. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signal associated with exercise-induced AKI in URAT1-uricase double-knockout mice was attenuated by uric-acid-lowering therapy using allopurinol or topiroxostat ^[9][56].

Fanconi syndrome is caused by generalized proximal tubular dysfunction and manifested by phosphaturia, renal glucosuria, aminoaciduria, tubular proteinuria, and proximal renal tubular acidosis ^[10][57]. It is secondary to systemic disease in many cases, and it is called renal Fanconi syndrome (RFS) when renal-limited. Because the proximal tubule is the only nephronal segment capable of handling uric acid in the kidneys, hypouricemia and hyperuricosuria are also important clues for the diagnosis of Fanconi syndrome.

The etiology of RFS includes inherited and acquired disorders and RFS, when diagnosed in adults, is most commonly associated with drug toxicity ^[11][58]. The frequently implicated agents include cisplatin, ifosfamide, tenofovir, sodium valproate, and aminoglycoside antibiotics ^[12][59]. When these drugs accumulate in the proximal tubular cells because of a traffic jam between the basolateral entrance and the apical exit, mitochondrial DNA depletion and dysfunction occur, which can ultimately cause a kind of proximal tubulopathy characterized by AKI and Fanconi syndrome ^[13][60].

With advances in molecular genetics, three genetic forms of RFS have been identified: Fanconi renotubular syndrome (FRTS) type 1, 2, and 3 ^[10][57]. These were previously considered to be idiopathic Fanconi syndrome, but cases of idiopathic adult-onset RFS are still being reported ^[14][61]. FRTS1 is inherited in an autosomal dominant fashion and associated with progressive kidney failure. The gene and gene product altered in FRTS1 have not been identified, but the gene locus for this disease was mapped to human chromosome 15q15.3 ^[15][62]. FRTS2 is characterized by phosphate wasting and rickets, and is caused by a mutation in SLC34A1, which encodes the phosphate transporter NaPi-IIa ^[16][63]. FRTS3 is the prototype of RFS characterized by no kidney failure ^[10][57] and the autosomal dominant inheritance of heterozygous missense mutation in the EHHADH gene ^[17][64].

Kidney involvement in patients with COVID-19 is common and can range from urinary abnormalities to AKI requiring kidney replacement therapy. The COVID-19-associated AKI is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19 ^[18][65]. According to kidney biopsies and autopsy series, acute tubular injury is the dominant renal pathology, although glomerular pathologies, such as collapsing glomerulopathy and thrombotic microangiopathy, have been found ^[19][66].

Although kidney damage may result from hemodynamic factors and dysfunctional immune responses in patients with COVID-19 ^[20][67], there is also some evidence of a direct kidney infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 was detected in the kidneys of patients with COVID-19 using immunohistochemistry, immunofluorescence, real-time reverse transcription–polymerase chain reaction, in situ hybridization, and electron microscopy ^[21][68]. Because the angiotensin-converting enzyme 2 receptor target of SARS-CoV-2 is highly expressed in proximal tubule cells, Werion et al. investigated specific manifestations of proximal tubule dysfunction in patients with COVID-19 ^[22][69]. In a cohort of 49 patients requiring hospitalization, low-molecular-weight proteinuria, neutral aminoaciduria, and the defective handling of uric acid or phosphate were found. Among these features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and a significant increase in the risk of respiratory failure, necessitating invasive mechanical ventilation. The authors also documented prominent proximal tubular injury with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Particles resembling coronaviruses were identified in the proximal tubular cells by transmission electron microscopy ^[22][69].

These results were validated by two independent cohorts involving 192 and 325 patients hospitalized with COVID-19 in Brussels, Belgium ^[23][70]. The same conclusion was drawn that in COVID-19 patients requiring hospitalization, hypouricemia is common and associated with disease severity and progression to respiratory failure. Similar findings were reported from a pediatric patient ^[24][71] and a Chinese cohort involving 1854 patients ^[25][72].

Several hyponatremic disorders are associated with altered serum uric acid levels. While the serum uric acid level is normal or elevated in hypovolemic hyponatremia, hypouricemia is typically associated with SIAD, CSW/RSW, and thiazide-induced hyponatremia.

Two supplemental features of water retention, serum uric acid < 4 mg/dL, and blood urea nitrogen (BUN) < 10 mg/dL, are very useful in the diagnosis of SIAD ^[26][73]. Hypouricemia in SIAD is the result of an increased uric acid clearance related to a reduction in proximal tubular uric acid reabsorption ^[27][74]. The correction of hyponatremia by water restriction normalizes uric acid clearance, despite the persistent inappropriate secretion of arginine vasopressin ^[28][75]. However, the mechanism of decreased tubular uric acid reabsorption in SIAD is unclear. In subjects with desmopressin-induced hyponatremia, the fractional excretion of uric acid was not elevated, unlike in hyponatremic patients with SIAD ^[29][76]. These results suggest a role of vasopressin V1 receptor (V1R) stimulation in the increase in renal uric acid clearance. Twenty years later, Taniguch et al. examined this hypothesis at the level of renal uric acid transporters ^[30][77] and showed that terlipressin-treated rats had a downregulation of GLUT9 (for uric acid reabsorption) and an upregulation of ABCG2 and NPT1 (for uric acid secretion) in association with hypouricemia and an increased fractional excretion of uric acid. It is also conceivable that the paracellular reabsorption of uric acid might be suppressed by V1R signaling in the proximal tubule.

CSW was first described in 1950 from three patients presenting with hyponatremia, clinical evidence of volume depletion (e.g., hypotension, unexplained tachycardia, low central venous pressure, pre-renal azotemia, hemoconcentration, or metabolic alkalosis), and renal sodium wasting in the setting of various forms of cerebral disease ^[31][78]. Additionally, intracranial pathologies were presumed to disrupt efferent neural pathways to the kidneys, resulting in salt wasting and hypovolemia. However, the accurate assessment of volume status is clinically unavailable, and achieving a differential diagnosis between CSW and SIAD is difficult. Both conditions present with hyponatremia with a low plasma osmolality, an inappropriately elevated urine osmolality, a urine sodium concentration usually > 40 mmol/L, and a low serum uric acid concentration due to an increased fractional excretion of uric acid ^[32][79]. Thus, CSW patients have an unusual combination of hypovolemia and hypouricemia.

Controversy regarding the existence and prevalence of CSW remains ^[33][80]. Despite seven decades of investigation, the pathophysiologic basis for the natriuresis and uricosuria of CSW is not yet proven. The general belief is that CSW rarely occurs and may be a subtype of SIAD ^[34][81]. However, Maesaka et al. reported that CSW is not rare and more often occurs in patients without cerebral diseases than those with cerebral diseases ^[35][82], and they proposed a change in the terminology from CSW to RSW ^[36][83]. In addition, these authors emphasized the characteristics of CSW/RSW in comparison to SIAD; specifically, hypouricemia and an increased fractional excretion of uric acid persist following the correction of hyponatremia ^[37][84], and this proximal tubular defect is often accompanied by an increased fractional excretion of phosphate ^[38][85]. Prospective studies of larger groups of patients are necessary to confirm the diagnostic significance of these parameters.

As described above, hyperuricemia can be induced by the use of thiazide and loop diuretics. However, hypouricemia is a characteristic laboratory finding when hyponatremia is induced by thiazide diuretics. Previous studies have shown that patients with thiazide-induced hyponatremia have clinical features of SIADH, including a low serum uric acid concentration and a low BUN level ^[39][86], and the mechanism of thiazide-induced hyponatremia can be explained by nephrogenic antidiuresis ^[40][87]. How uric acid transport is disturbed by thiazide-induced renal water retention remains to be answered.