Altered Serum Uric Acid Levels in Kidney Disorders

Abstract

Serum uric acid levels are altered by kidney disorders because the kidneys play a dominant role in uric acid excretion. Here, major kidney disorders which accompany hyperuricemia or hypouricemia, including their pathophysiology, are discussed. Chronic kidney disease (CKD) and hyperuricemia are frequently associated, but recent clinical trials have not supported the pathogenic roles of hyperuricemia in CKD incidence and progression. Diabetes mellitus (DM) is often associated with hyperuricemia, and hyperuricemia may be associated with an increased risk of diabetic kidney disease in patients with type 2 DM. Sodium-glucose cotransporter 2 inhibitors have a uricosuric effect and can relieve hyperuricemia in DM. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an important hereditary kidney disease, mainly caused by mutations of uromodulin (UMOD) or mucin-1 (MUC-1). Hyperuricemia and gout are the major clinical manifestations of ADTKD-UMOD and ADTKD-MUC1. Renal hypouricemia is caused by URAT1 or GLUT9 loss-of-function mutations and renders patients susceptible to exercise-induced acute kidney injury, probably because of excessive urinary uric acid excretion. Hypouricemia derived from renal uric acid wasting is a component of Fanconi syndrome, which can be hereditary or acquired. During treatment for human immunodeficiency virus, hepatitis B or cytomegalovirus, tenofovir, adefovir, and cidofovir may cause drug-induced renal Fanconi syndrome. In coronavirus disease 2019, hypouricemia due to proximal tubular injury is related to disease severity, including respiratory failure. Finally, serum uric acid and the fractional excretion of uric acid are indicative of plasma volume status; hyperuricemia caused by the enhanced uric acid reabsorption can be induced by volume depletion, and hypouricemia caused by an increased fractional excretion of uric acid is the characteristic finding in syndromes of inappropriate anti-diuresis, cerebral/renal salt wasting, and thiazide-induced hyponatremia. Molecular mechanisms by which uric acid transport is dysregulated in volume or water balance disorders need to be investigated.

Keywords: COVID-19; Fanconi syndrome; autosomal dominant tubulointerstitial kidney disease; chronic kidney disease; hyperuricemia; hyponatremia; hypouricemia.

Figure 1

Major transporters for uric acid reabsorption and secretion in the proximal tubule. (A): Na⁺-dependent anion transport increases intracellular concentrations of anions that exchange with luminal urate by URAT1. GLUT9 acts as the basolateral exit for urate reabsorption. (B): OAT1 and OAT3 transport urate through the basolateral membrane in exchange with α-KG. At the apical membrane, urate is secreted via ABCG2, NPT1, and/or NPT4. Abbreviations: ABCG2, ATP-binding cassette subfamily G member 2; GLUT9, glucose transporter 9; α-KG, α-ketoglutarate; NPT1, sodium-phosphate cotransporter 1; NPT4, sodium-phosphate cotransporter 4; OAT1, organic anion transporter 1; OAT3, organic anion transporter 3; SGLT2, sodium-glucose cotransporter 2; URAT1, urate transporter 1.

Figure 2

Serum uric acid levels according to changes in eGFR. As eGFR decreases in patients with chronic kidney disease, the serum uric acid level tends to increase. Abbreviation: eGFR, estimated glomerular filtration rate. Adapted from the article by Oh et al. [12] according to the Creative Commons Attribution 4.0 International License.

Figure 3

Potential mechanisms by which SGLT2 inhibitors increase uricosuria in the proximal tubule. URAT1 and GLUT9 are the major pathways for uric acid reabsorption. When SGLT2 is inhibited by SGLT2 inhibitors, GLUT9b is overwhelmed by excessive glucose and its capacity for uric acid transport is diminished. SGLT2 inhibitors can also inhibit URAT1, further increasing uricosuria. Abbreviations: GLUT9, glucose transporter 9; SGLT2, sodium-glucose cotransporter 2; URAT1, urate transporter 1.

Figure 4

Potential mechanisms by which thiazide and loop diuretics reduce uricosuria in the proximal tubule. URAT1 is the major transporter for uric acid reabsorption, and OAT1 and NPT4 are the major pathways for uric acid secretion. Thiazide and loop diuretics enter the proximal tubular cell basolaterally via OAT1 and OAT3 and exit via apically located URAT1 or NPT4. Competitive binding between diuretics and uric acid for the basolateral OAT1 and OAT3 and apical NPT4 would reduce uric acid secretion by the proximal tubule. The apically located URAT1 acts as an anion exchanger and may reabsorb uric acid in exchange for the secretion of thiazide or loop diuretics. Thus, a decrease in uric acid secretion, as well as an increase in uric acid reabsorption by the proximal tubule, will lead to diuretic-induced hyperuricemia. Abbreviations: GLUT9, glucose transporter 9; NPT4, sodium-dependent, inorganic phosphate transporter 4; OAT1, organic anion transporter 1; OAT3, organic anion transporter 3; URAT1, urate transporter 1.