In this report, we present, for the first time, two cases of patients with HAPC who were born at low altitudes and developed ureteral calculi while residing at high altitudes. According to the chronic mountain sickness (CMS) Qinghai integral standard of the 6th Plateau Medicine Conference in 2004 (6), the CMS integral of patients 1 and 2 were 8 and 12 points, respectively. Both cases presented with acute ureteral colic as the first symptom and increased serum uric acid levels. In light of the aforementioned data, we speculate that polycythemia may be a risk factor for ureteral calculi in individuals who migrate to the highlands. To the best of our knowledge, this is the first report that presents the occurrence of HAPC with ureteral calculi in migrants to the highlands.
The etiology of ureteral calculi remains unknown and is related to geographical locations, climatic environments, dietary habits, occupations, and basic diseases (7). Ureteral calculi account for 65% of urinary calculi and the incidence has been rising recently (8). It is well accepted that hyperuricemia significantly increases the incidence of urinary calculi (9). When the uric acid concentration is supersaturated, it gets deposited in the renal tissues in the form of sodium urate crystals. Researchers have found that there was a 75% incidence rate of urinary tract stones in patients with hyperuricemia caused by rare single-gene enzyme disorders (10).
Uric acid is the end-product of purine nucleotide metabolism and approximately two-thirds of uric acid excretion occurs through the urine (11). Hyperuricemia is a common condition in patients with HAPC and multiple factors contribute to this process. Excessive erythrocyte proliferation and apoptosis of HAPC may contribute to increased uric acid levels (12). Hyperuricemia is also commonly found in patients with erythrocytosis secondary to lung diseases and polycythemia vera (13, 14), which indirectly indicates the correlation between erythrocytosis and uric acid. Moreover, the filtration function of the kidneys can be inhibited by increased blood viscosity. In addition, high-altitude hypoxia increases the concentration of lactic acid, especially in patients with HAPC, which can competitively inhibit the excretion of uric acid (15).
A high uric acid concentration and the persistent low pH of urine play a key role in the pathogenesis of uric acid calculi (5). Urine pH can affect the formation of different types of urinary stones. Under normal circumstances, urine pH is approximately 5.7–6.3. Consequently, a uric acid calculus is easy to form when the urine pH is < 5.5, while calcium phosphate and struvite calculi readily form when the urine pH is high (16, 17). In addition to pure uric acid stones, uric acid or sodium urate precipitation provides a nidus for the subsequent formation of calcium oxalate stones, thereby further contributing to the overall incidence of stones (18). Individuals are at risk of developing hyperventilation and respiratory alkalosis when they are exposed to acute hypoxia, although their pH is kept within a normal range (19). Moreover, the formation of urinary calculi has a relatively slow progress rate, and hence, acute hypoxic exposure has a limited effect on urinary stone formation. However, for patients with HAPC who are exposed to chronic hypoxia, a high uric acid concentration plays an important role in the formation of uric acid stones. Moreover, the concentrations of uric acid metabolites in such patients are increased, and uric acid crystals are apt to precipitate and deposit in the kidneys. A urinary calculus is formed in patients with HAPC, which in turn aggravates the renal excretion function that can ultimately lead to uric acid formation thereby continuing a vicious circle.
The prevention of ureteral calculi associated with HAPC is particularly important for several reasons. First, in routine blood investigations, the serum uric acid level and 24-h urinary pH should be regularly monitored in individuals who have migrated to the high-altitude areas. Second, drinking plenty of water is recommended because a large amount of liquid intake has a protective effect on the incidence of urolithiasis. Third, the dietary structure should be appropriately adjusted by reducing the intake of foods with high purine content. It is worth noting that type II diabetes, metabolic syndrome, and obesity are associated with hyperuricemia, and are also the risk factors for uric acid stone formation (20). Therefore, people with these diseases entering the plateau should monitor the uric acid levels in order to reasonably prevent the occurrence of urolithiasis.
Urolithiasis associated with HAPC might be a public health concern worldwide. Implementation of a system to monitors serum uric acid levels in individuals residing in high-altitude areas could help prevent ureteral calculi associated with HAPC. Meanwhile, publicity and education on this matter should be strengthened to improve the dietary structure and develop the habit of drinking plenty of water. Further research on the underlying mechanisms of urinary stone formation in patients with HAPC, including stone analysis and 24-h urine composition analysis could provide useful information regarding the association between urinary stone formation and HAPC.