Purines (adenine and guanine) and pyrimidines (cytosine, thymine, uracil) serve fundamental roles in the replication of genetic material, gene transcription, protein synthesis, and cellular metabolism. Disorders that involve abnormalities of nucleotide metabolism range from relatively common diseases such as hyperuricemia and gout, in which there is increased production or impaired excretion of a metabolic end product of purine metabolism (uric acid), to rare enzyme deficiencies that affect purine and pyrimidine synthesis or degradation. Understanding these biochemical pathways has led, in some instances, to the development of specific forms of treatment, such as the use of allopurinol, to reduce uric acid production.
Uric acid is the final breakdown product of purine degradation in humans. It is a weak acid with pKas of 5.75 and 10.3. Urates, the ionized forms of uric acid, predominate in plasma extracellular fluid and synovial fluid, with ˜98% existing as monosodium urate at pH 7.4.
Plasma is saturated with monosodium urate at a concentration of 405 μmol/L (6.8 mg/dL) at 37°C. At higher concentrations, plasma is therefore supersaturated, creating the potential for urate crystal precipitation. However, plasma urate concentrations can reach 4800 μmol/L (80 mg/dL) without precipitation, perhaps because of the presence of solubilizing substances.
The pH of urine greatly influences the solubility of uric acid. At pH 5.0, urine is saturated with uric acid at concentrations ranging from 360 to 900 μmol/L (6–15 mg/dL). At pH 7, saturation is reached at concentrations between 9480 and 12,000 μmol/L (158 and 200 mg/dL). Ionized forms of uric acid in urine include mono- and disodium, potassium, ammonium, and calcium urates.
Although purine nucleotides are synthesized and degraded in all tissues, urate is produced only in tissues that contain xanthine oxidase, primarily the liver and small intestine. Urate production varies with the purine content of the diet and the rates of purine biosynthesis, degradation, and salvage (Fig. 359-1). Normally, two-thirds to three-fourths of urate is excreted by the kidneys, and most of the remainder is eliminated through the intestines.
The total-body urate pool is the net result between urate production and excretion. Urate production is influenced by dietary intake of purines and the rates of de novo biosynthesis of purines from nonpurine precursors, nucleic acid turnover, and salvage by phosphoribosyltransferase activities. The formed urate is normally excreted by urinary and intestinal routes. Hyperuricemia can result from increased production, decreased excretion, or a combination of both mechanisms. When hyperuricemia exists, urate can precipitate and deposit in tissues as tophi.
The kidneys clear urate from the plasma and maintain physiologic balance by utilizing specific organic anion transporters (OATs), including urate transporter 1 (URAT1) and human uric acid transporter (hUAT) (Fig. 359-2). URAT1 and other OATs carry urate into the tubular cells from the apical side of the lumen. Once inside the cell, urate must pass to the basolateral side of the lumen in a process controlled by the voltage-dependent carrier hUAT. Until recently, a four-component model has been used to describe the renal handling of urate/uric acid: (1) glomerular filtration, (2) tubular reabsorption, (3) secretion, and (4) postsecretory reabsorption. Although these processes have been considered sequential, it is now apparent that they are carried out in parallel by these transporters. URAT1 is a novel transporter expressed at the apical brush border of the proximal nephron. Uricosuric compounds (Table 359-1) directly inhibit URAT1 on the apical side of the tubular cell (so-called cis-inhibition). In contrast, antiuricosuric compounds (those that promote hyperuricemia), such as nicotinate, pyrazinoate, lactate, and other aromatic organic acids, serve as the exchange anion inside the cell, thereby stimulating anion exchange and urate reabsorption (trans-stimulation). The activities of URAT1, other OATs, and sodium anion transporter result in 8–12% of the filtered urate being excreted as uric acid.
Schematic for handling of uric acid by the kidney. A complex interplay of transporters on both the apical and basolateral aspects of the renal tubuleepithelial cell is involved in the reabsorption of uric acid. Please see text for details. Most uricosuric compounds inhibit URAT1 on the apical side, as well as OAT1, OAT3, and GLUT9 on the basolateral side.
Table 359-1 Medications with Uricosuric Activity
Most children have serum urate concentrations of 180– 240 μmol/L (3–4 mg/dL). Levels begin to rise in males during puberty but remain low in females until menopause. Mean serum urate values of adult men and premenopausal women are 415 and 360 μmol/L (6.8 and 6 mg/dL), respectively. After menopause, values for women increase to approximate those of men. In adulthood, concentrations rise steadily over time and vary with height, body weight, blood pressure, renal function, and alcohol intake.
Hyperuricemia can result from increased production or decreased excretion of uric acid or from a combination of the two processes. Sustained hyperuricemia predisposes some individuals to develop clinical manifestations including gouty arthritis (Chap. 333), urolithiasis, and renal dysfunction (see below).
Hyperuricemia is defined as a plasma (or serum) urate concentration >405 μmol/L (6.8 mg/dL). The risk of developing gouty arthritis or urolithiasis increases with higher urate levels and escalates in proportion to the degree of elevation. Hyperuricemia is present in between 2 and 13.2% of ambulatory adults and is even more frequent in hospitalized individuals.