Consult Rounds: Topiramate and the Kidney

Topiramate was first introduced to treat seizures but now is increasingly used to treat migraines and is among the top 6 drugs sold in the United States. In addition, it is used as a weight loss agent as well. Renal toxicity with this agent is not uncommon.

The three forms of renal toxicity are:

Kidney Stones

Renal Tubular Acidosis

Isolated hypokalemia

A study in 2006 published in AJKD showed that topiramate acts through multiple mechanisms, 1 of which is the inhibition of carbonic anhydrase, as in vitro studies have shown. Several case reports described a link between topiramate and the formation of calcium phosphate stones, but the mechanism for this is largely unknown.

The authors conclude that taking topiramate for about 1 year caused systemic metabolic acidosis, significantly increased urine pH, and markedly lowered urine citrate — changes that increase the propensity to form calcium phosphate stones.

With the increasing use of topiramate, reports have emerged that topiramate can cause metabolic acidosis in some patients. It does this by impairing both the normal reabsorption of filtered HCO(3)(-) by the proximal renal tubule and the excretion of H(+) by the distal renal tubule. This combination of defects is termed mixed proximal and distal RTA. Topiramate-induced RTA can make patients prone to kidney stones as stated earlier as well.  The utility of regular monitoring of HCO(3)(-) levels has not been proven and is not routine practice currently.

Finally, isolated refractory renal wasting of potassium has also been reported with this agent.

A large systematic review confirmed the above findings of renal toxicity with this agent. Fourty-seven reports published between 1996 and 2013 were retained for the final analysis. Five case-control studies and six longitudinal studies addressed the effect of topiramate on acid-base and potassium balance. A significant tendency towards mild-to-moderate hyperchloraemic metabolic acidosis (with bicarbonate ≤21.0 mmol l(-1) in approximately every third case) and mild hypokalaemia (with potassium ≤3.5 mmol l(-1) in 10% of the cases) was noted on treatment with topiramate, which was similar in children and adults.

Finally,increasing evidence supports the use of topiramate. Topiramate is generally well tolerated, and serious adverse events are rare. Nonetheless, it is linked with the development of acidosis, hypokalaemia, hyperuricaemia and hypocitraturia and eventually renal stones.