Wednesday, September 26, 2012

The Good the Bad and the Ugly - Uric Acid and the Kidney

At some point during evolution humans lost the enzyme uricase and during the long and tedious process of getting to the modern age and this was initially a good thing. Uric acid accumulation as a result of uricase loss is thought to have been protective in situations of hypotension in low salt environments, conferred increased intelligence and reduced oxidant stress (although some authors consider this highly speculative). The Nephrologist often has a role in managing gout, since uric acid is mainly excreted by the kidney.

So now that we do not have a shortage of salt anymore and our diet is rich in purines we get to see the drawbacks of evolution. This comes in the unpleasant form of gout. Most of the time, gout is caused by under-excretion of uric acid by the kidney and only in the minority of cases (~10%) by overproduction. Renal uric acid handling is complicated and about a decade ago a transporter with specific apical urate-anion exchange activity was described.

Gout can be triggered by a number of gluttonous habits:
  • Alcohol - causes increased urate synthesis and increased lactate production which increases urate reabsorption
  • Foods high in purines increase uric acid levels.
  • Lead causes increased uric acid levels by impairing urate excretion, which is associated with the development of gout (termed “saturnine gout”). This was much more common in older days when lead ingestion was high.
  • Dietary fructose acutely raises serum uric acid levels.
Therefore gout was considered a "true nobleman's disease" in earlier centuries and artists such as William Hogart used to portray them in their works.

Now some people are worse off because they have to take medications that cause hyperuricemia. Amongst them are transplant patients depending on immunosuppressants and diuretics, for example a heart transplant patient whom I recently saw in clinic.

Cyclosporine: Decreased GFR and possibly tubular damage contribute to cyclosporine induced uric acid retention. Tacrolimus does not offer any advantage over cyclosporine. A study in children with transplants concluded that cyclosporine induced tubular reabsorption of uric acid.

Diuretics:HCTZ is a common trigger of gout attacks but all other diuretics also do. Rising serum uric acid with diuretic use occurs with low doses and increases dose-dependently. Volume depletion stimulates a marked increase in proximal tubular reabsorption of urate. The mechanisms involved in the regulation of urate reabsorption by extracellular volume status are however unclear. Furosemide can induce hyperlacticacidemia sufficient to suppress tubular excretion of urate. Diuretics have also been shown to interfere directly with uric acid handling by the kidney. Loop diuretics and thiazides have been shown to directly inhibit NPT4-mediated urate secretion and furosemide can inhibit urate uptake by URAT1.

Management is aimed at lowering serum uric acid levels with Allopurinol or Febuxostat. Febuxostat is an alternative to allopurinol in patients with allopurinol intolerance or hypersensitivity.  In my (limited) experience uricosuric drugs such as Probenecid are rarely used in practice anymore and the teaching is that they actually can trigger acute gout attacks by initially decreasing excretion. Pegloticase, a pegylated recombinant porcine-like uricase, can be given in severe cases when Allopurinol or Febuxostat are not effective. The drug needs to be given IV but thanks to its long half-life only every 2-4 weeks.

Posted by Florian Toegel

1 comment:

  1. This is very important and useful information. Thanks for sharing it.
    Reduce Uric Acid

    ReplyDelete

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