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

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At some point duringevolution humans lost the enzyme uricase and during the long and tediousprocess of getting to the modern age and this was initially a good thing. Uricacid accumulation as a result of uricase loss is thought to have been protectivein situations of hypotension in low salt environments, conferred increasedintelligence and reduced oxidant stress (although some authors consider thishighly speculative). The Nephrologist often has a role in managing gout, sinceuric acid is mainly excreted by the kidney.
So now that we do nothave a shortage of salt anymore and our diet is rich in purines we get to seethe drawbacks of evolution. This comes in the unpleasant form of gout. Most ofthe time, gout is caused by under-excretion of uric acid by the kidney and onlyin the minority of cases (~10%) by overproduction. Renal uric acid handling iscomplicated and about a decade ago a transporter with specific apicalurate-anion exchange activity was described.
Gout can be triggeredby a number of gluttonous habits:

• Alcohol - causesincreased urate synthesis and increased lactate production which increasesurate reabsorption
• Foods high in purinesincrease uric acid levels.
• Lead causes increaseduric acid levels by impairing urate excretion, which is associated with thedevelopment of gout (termed “saturnine gout”). This was much more common inolder days when lead ingestion was high.
• Dietary fructoseacutely raises serum uric acid levels.

Therefore gout wasconsidered a "true nobleman's disease" in earlier centuries andartists such as William Hogart used to portray them in their works.
Now some people areworse off because they have to take medications that cause hyperuricemia. Amongstthem are transplant patients depending on immunosuppressants and diuretics, forexample a heart transplant patient whom I recently saw in clinic.
Cyclosporine: DecreasedGFR and possibly tubular damage contribute to cyclosporine induced uric acidretention. Tacrolimus does not offer any advantage over cyclosporine. A studyin children with transplants concluded that cyclosporine induced tubularreabsorption of uric acid.
Diuretics:HCTZ is acommon trigger of gout attacks but all other diuretics also do. Rising serumuric acid with diuretic use occurs with low doses and increasesdose-dependently. Volume depletion stimulates a marked increase in proximaltubular reabsorption of urate. The mechanisms involved in the regulation ofurate reabsorption by extracellular volume status are however unclear. Furosemidecan induce hyperlacticacidemia sufficient to suppress tubular excretion ofurate.Diuretics have also been shown to interfere directly with uric acid handling bythe kidney. Loop diuretics and thiazides have been shown to directly inhibitNPT4-mediated urate secretion and furosemide can inhibit urate uptake by URAT1.
Management is aimedat lowering serum uric acid levels with Allopurinol or Febuxostat. Febuxostatis an alternative to allopurinol in patients with allopurinol intolerance orhypersensitivity.  In my (limited)experience uricosuric drugs such as Probenecid are rarely used in practice anymoreand the teaching is that they actually can trigger acute gout attacks byinitially decreasing excretion. Pegloticase, a pegylated recombinantporcine-like uricase, can be given in severe cases when Allopurinol orFebuxostat are not effective. The drug needs to be given IV but thanks to itslong half-life only every 2-4 weeks.
Posted by Florian Toegel