The previous concept of urate proximal tubular reabsorption, secretion, and postsecretory reabsorption has been revised based on recent studies using molecular biologic and genetic techniques. These investigations have shown that there are a number of organic anion transporters in the proximal tubule that participate in urate reabsorption, some on the basolateral and some on the apical surface. An important organic anion transporter known as URAT1 is highly specific for urate transport and exchanges urate for other organic anions. URAT1 is localized to the apical surface of proximal tubular cells and exchanges urate through a non-voltage dependent mechanism. A number of uricosuric medications bind to URAT1, including probenecid, indomethacin, and salicylates.10 Unique to angiotensin receptor blockers, losartan inhibits the URAT1 transporter,11 resulting in increased urinary urate excretion and decreased serum urate levels.12 Individuals with mutations in the URAT1 transporter have low serum urate levels, very elevated urinary urate levels, and are prone to acute kidney failure13 and uric acid urolithiasis.14
While there are a number of organic anion transporters in the proximal tubule, the cumulative effect is extensive urate reabsorption that is linked to sodium reabsorption. It is of great practical importance for the clinician to realize that increased proximal tubular sodium reabsorption leads to increased urate reabsorption and hyperuricemia.
Gout occurs almost exclusively in individuals with hyperuricemia, but only a minority of individuals with hyperuricemia develop gout. The probability of developing gout increases with increasing serum urate levels.
The vast majority of individuals who suffer from gout are under-excreters of uric acid, and hyperuricemia is predominantly the result of reduced renal clearance of urate. The development of chronic kidney disease, even when mild, may be associated with decreased urate excretion and hyperuricemia. As renal failure progresses, hyperuricemia worsens.
Factors that stimulate proximal tubular reabsorption of urate will also increase serum urate levels. As mentioned previously, increased proximal sodium reabsorption is a primary driver of proximal urate reabsorption. The following are known to cause increased proximal sodium reabsorption:
Congestive heart failure. While there are a number of mechanisms that may be responsible, increased proximal tubular sodium uptake with secondary increased proximal tubular urate uptake is a known factor. Higher serum urate levels in these patients predict a worse outcome.15
Use of Diuretics. Diuretics lead to increased sodium losses in the thick ascending limb or distal tubule. The nephron compensates for this by increasing proximal tubular sodium reabsorption and secondarily increasing proximal tubular urate reabsorption.
Aspirin use. Low-dose aspirin increases proximal tubular urate reabsorption in the elderly. At a dosage of 75 mg/day, aspirin was found to cause a 15% decrease in urate excretion in elderly in-patients in hospital.16
Genetic Disorders. Some genetic disorders are associated with increased proximal tubular reabsorption of urate. Patients with uromodulin associated kidney disease have mutations in the gene encoding uromodulin (Tamm Horsfall protein).17 The disease is inherited in an autosomal dominant manner. Mutations in uromodulin decrease the ability to reabsorb sodium in the thick ascending limb, resulting in increased proximal tubular sodium uptake and, secondarily, uric acid. Individuals present with hyperuricemia in childhood and often develop gout in their teenage years. Chronic kidney failure develops over time, with patients developing end-stage renal disease in the 4th through 8th decades of life. Hyperuricemia does not cause the chronic kidney disease (CKD) in this condition, and allopurinol does not stop progression of kidney failure, though it may slow progression.
Autosomal dominant mutations in the gene encoding renin have also been associated with hyperuricemia. Mutations in renin result in mild hyperkalemia, anemia, and hyperuricemia beginning in youth. Hyperuricemia is due to increased proximal tubular urate reabsorption, but the cause of this is uncertain. Patients with this condition also develop slowly progressive CKD.
It is important for the nephrologist to be able to identify potential mechanisms in individual patients that lead to increased proximal tubular urate reabsorption so as to better treat hyper-uricemia and gout.
While reduced urate excretion is the predominant factor, increased urate production still remains problematic, and is frequently secondary to consumption of meat products18 and alcohol.19, 20 Beer has a high nucleic acid content that leads to increased urate levels.20, 21
Kidney transplantation is associated with a high prevalence of gout,22 due to factors including decreased glomerular filtration in transplanted kidneys, frequent diuretic use, and the hypouricosuric effects of cyclosporine and tacrolimus. Cyclosporine is more likely to be associated with gout than tacrolimus.23 Importantly, allopurinol and febuxostat should not be used in patients receiving azathioprine, as this can lead to life-threatening leucopenia.