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

CLICK HERE TO GET CISTANCHE FOR TREATMENTS

1. Introduction

Uric acid is the end-product of purine metabolism in humans and apes, unlike other mammals which have uricase. This genetic evolution has led humans to exhibit plasma uric acid levels that are 3–10 times higher than those of other mammals [1]. We recently analyzed data from the Korean Genome and Epidemiology Study (which enrolled 58,981 men and 113,989 women) and found that the mean serum uric acid level was higher in men (5.7 mg/dL) than in women (4.2 mg/dL). When hyperuricemia and hypouricemia were defined as serum uric acid levels > 7 mg/dL and ≤2.0 mg/dL, respectively, their prevalence rates differed according to age and sex. Noticeably, the prevalence of hyperuricemia increased with aging in women but not in men. Overall, the prevalence rates of hyperuricemia in men and women were 133 and 8 per 1000 people, respectively, while the prevalence rates of hypouricemia in men and women were 1 and 6 per 1000 people, respectively [2]. Estrogen may play a protective role in hyperuricemia by regulating the activity of uric acid

transporters in the kidney (3]. This enhances the renal clearance of uric acid and may be linked to decreased cardiovascular risk. These altered serum uric acid levels may have clinical impacts. In a large cohort study of Korean men and women, both low and high uric acid levels were associated with an increased mortality rate, supporting a J-shaped relationship between serum uric acid and adverse clinical outcomes (4 .)

BEST HERBS FOR CKD

Serum uric acid levels are normally maintained by the balance between hepatic production and renal and intestinal excretion. Purines, derived from diet (100-200 mg/day and the cellular metabolism of nucleic acids (500-600 mg/day), are metabolized to uric acid in the liver The final step of uric acid synthesis (700 mg/day) is catalyzed by the enzyme xanthine oxidase, and xanthine oxidase inhibitors, such as allopurinol and febuxostat, are clinically useful in lowering uric acid. The kidneys play a dominant role in uric acid excretion because they excrete approximately 70% of the uric acid produced daily (500 mg/day)while the remaining 30% (200 mg/day) is excreted by the intestine [5]. Normally, 90% of glomerular-filtered uric acid is reabsorbed by the proximal tubule. However, uric acid transport in the proximal tubule is bidirectional (Figure 1); reabsorption is mainly mediated by apically located urate transporter 1 (URAT1) and basolaterally located glucose transporter 9 (GLUT9), and secretion is exerted by basolaterally located organic anion transporters 1 and 3 (OAT1, OAT3) and apically located ATP-binding cassette superfamily G member 2 (ABCG2) and sodium-dependent, inorganic phosphate trans. porters 1 and 4 (NPT1,NPT4). Considering the usual ranges of the fractional excretion of uric acid, the transporters that mediate uric acid reabsorption may be more influential than those mediating uric acid secretion (6). Most uricosuric agents, such as benzbromaroneprobenecid, and lesinurad, inhibit URAT1 7].

BEST HERBS FOR CKD

Figure 1. Major transporters for uric acid reabsorption and secretion in the proximal tubules): 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 a-KC. 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: a-KG, a-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

BEST HERBS FOR CKD

Among the angiotensin Il receptor blockers, losartan has uricosuric action. In hypertensive patients, losartan decreases serum uric acid in association with a concomitant increase in urinary uric acid excretion. However, losartan does not affect serum and urine uric acid levels in hypertensive patients with a loss-of-function mutation of URAT1 (8suggesting that losartan inhibits URAT1 in the proximal tubule. The uricosuric action of losartan may be affected by URAT1 gene polymorphisms [9,10].

BEST HERBS FOR CKD

Declines in the glomerular filtration rate (GFR) and/or the dysregulation of the proximal tubular transport can lead to altered serum uric acid levels. In this paper, the associations between kidney disorders and altered serum uric acid levels are discussed. Both hyperuricemia and hypouricemia are frequently found in primary or secondary kidney diseases (Table 1). Chronic kidney disease (CKD) is commonly associated with primary or secondary hyperuricemia. Diabetes mellitus (DM) is often accompanied by hyperuricemia, irrespective of kidney dysfunction. Hyperuricemia is an important clinical presentation of autosomal dominant tubulointerstitial kidney disease (ADTKD), a rare genetic cause of CKD. Other hereditary or acquired proximal tubular defects can present with hypouricemia. While hyperuricemia may be associated with volume depletion, hypouricemia is a characteristic finding in syndromes of inappropriate antidiuresis (SIAD), cerebral/renal salt wasting (CSW/RSW), and thiazide-induced hyponatremia. This review focuses on the role of the kidneys in the pathogenesis of hyperuricemia and hypouricemia, but primary gout and uric acid nephropathy will not be covered. In gout, chronic gouty nephropathy is an important cause of chronic tubulointerstitial nephritis, causing CKD. In tumor lysis syndrome, acute uric acid nephropathy can be complicated, leading to acute kidney injury (AKI).

Table 1. Major kidney disorders that accompany altered serum uric acid levels.

BEST HERBS FOR CKD