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