Uric Acid and Urate in Urolithiasis: The Innocent Bystander, Instigator, and Perpetrator

Abstract

Uric acid is an end product of purine metabolism in human beings. An unusual and still unexplained phenomenon is that higher primates have relatively high uric acid levels in body fluids owing to a combination of absence of degradation and renal retention. The physiologic purpose of high uric acid levels still is enigmatic, but the pathobiologic burden is a variety of crystallopathies owing to the low aqueous solubility of uric acid such as gouty arthritis and acute uric acid nephropathy. In the urinary space, three distinct conditions result from chronic uric acid and/or urate precipitation. The first and most common variety is uric acid urolithiasis. In this condition, urate is a victim of a systemic metabolic disease in which increased acid load to the kidney is coupled with diminished urinary buffer capacity owing to defective ammonium excretion, resulting in titration of urate to its sparingly soluble protonated counterpart, uric acid, and the formation of stones. Uric acid is the innocent bystander of the crime. The second variety is hyperuricosuric calcium urolithiasis, in which uric acid confers lithogenicity via promotion of calcium oxalate precipitation by multiple mechanisms involving soluble, colloidal, and crystalline urate salts. Uric acid is the instigator of the crime. The third and least common condition involves urate as an integral part of the urolith as an ammonium salt driven by high ammonium and high urate concentrations in urine. Here, uric acid is one of the perpetrators of the crime. Both known and postulated pathogenesis of these three types of urolithiasis are reviewed and summarized.

Keywords: Kidney stones; ammonium urate; calcium; hyperuricosuric; uric acid urolithiasis.

Figure 1:. Uric acid biology.

A. History of primate order evolution over 80 million years and subdivision into families. Progressive rise in uric acid levels parallels the loss of uricase activity from prosimians to humans. B. The rise in serum uric acid concentration is compared to urine uric acid-to-creatinine concentration; fractional excretion of urate was only available in very few species.

Figure 2:. Uric acid chemistry.

A. Uric acid exists in two keto-enol tautomers with the clinically relevant tautomers being the lactim (enol) form. There are two dissociable H+ giving rise to acid urate and urate (often just called urate) with pKa1 =5.4 and pKa2 = 9.8; the former being relevant in mammalian urine with the latter not present in human physiologic states. Under extreme conditions of UpH (e.g. urea-splitting organism in the urinary tract), some divalent urate may be present. Monovalent urate can pair with ambient cations (Cat+). B. Relative solubilities of uric acid and three urate salts as function of pH.

Figure 3:. Proposed multi-organ model of uric acid stone formation driven by aciduria.

Organic (H⁺; OA⁻ organic anion) acid load due to increased production and uptake by gut lumen exacerbated by decreased hepatic metabolism and increased production. This poses an increased acid load to the kidney, which is capable of excreting the acid. However, impairment of ammonia synthesis and ammonium excretion mandates carriage of H⁺ by alternative buffers (B); one of which is urate (Ur⁻) which when protonated, forms the insoluble uric acid.

Figure 4:. Pathophysiology of huperuricosuric calcium urolithiasis.

In the solution phase, sodium urate is a potent salting out agent that can increase the activity product of calcium oxalate. In the colloidal phase, sodium urate can adsorb and remove inhibitors of calcium oxalate crystallization. Finally, sodium urate crystals can initiate calcium oxalate crystallization via heterogeneous nucleation or epitaxy.

Figure 5:. Model for pathogenesis of ammonium acid urate stones.

Contributors to high urine ammonium include physiologic response to acid load and intraluminal generation of ammonium from urea. One of the byproduct of ureolysis is HCO₃⁻/CO₃²−, which also alkalinizes the urine. Increased endogenous or exogenous purine load and metabolism leads to increased uric acid generation, and the high urine pH (UpH) ensures that urate form is preferred.