Cidofovir nephrotoxicity and Probenecid

I recently saw an interesting case. A woman was being treated with cidofovir for adenovirus which was presumed to be responsible for an acute cardiomyopathy. Concurrent with cidofovir, she was also receiving probenecid for renoprotection, which I was not familiar with.

Cidofovir is a nucleotide analogue used primarily to treat CMV retinitis in patients with AIDS. However, cidofovir is also used to treat a number of DNA viruses including adenovirus. The main toxicity of cidofovir is nephrotoxicity, which can manifest as AKI, proteinuria, or a Fanconi-type syndrome with proximal tubular dysfunction. Nephrotoxicity can be reduced by co-administration with iv fluids and probenecid (the dosing regimen for the latter is 2g po 3 hours prior to the dose, then 1 g po 2 hours and 8 hours after.

How does probenecid reduce cidofovir nephrotoxicity? Over 80% of cidofovir is excreted unchanged in the urine in 24 hours. Most of this occurs via glomerular filtration, but cidofovir is also actively taken up from blood by the kidneys via the "organic anion transporter" located on the basolateral side of renal proximal tubular cells, and is then more slowly secreted into the tubular lumen. Renal clearance of cidofovir therefore exceeds the corresponding GFR.

The relatively slow secretion of cidofovir into the tubular lumen, in comparison to uptake from the blood, results in a long intracellular half-life of the drug in the proximal tubular cells which appears to underlie the nephrotoxicity. Probenecid, by inhibiting the organic anion transporter, prevents tubular uptake and protects the kidneys. This was demonstrated nicely in a pilot study in HIV patients. Interestingly, and somewhat paradoxically, this means that probenecid reduces nephrotoxicity while also DECREASING the renal clearance of the drug and thus INCREASING serum cidofovir concentrations as much as two-fold.

Probenecid is a banned drug for athletes for a related reason - because it blocks entry of certain drugs into the urine, it has been used as a masking agent for other banned performance-enhancing drugs including steroids. 

Posted by David Leaf

Renal Grand Rounds - A Chilling Case of Hyperkalemia

A 62 year old man with ischemic cardiomyopathy (EF 35%) and CKD (baseline Cr ~3 mg/dl) had a witnessed out-of-hospital cardiac arrest.  EMS arrived within 3 minutes.  He received CPR and was shocked out of ventricular fibrillation (VF).  He was intubated and therapeutic hypothermia was initiated in the field. He was admitted to the CCU, where therapeutic hypothermia was continued for 24 hours.  He received aggressive KCl repletion for hypokalemia (see graph below) and supraventricular arrhythmias.  On the second hospital day the patient was rewarmed, developed severe DIC (INR 10), worsening shock requiring 3 pressors, and renal was consulted for hyperkalemia and oliguric AKI on CKD.

Clinical pearls: Hypokalemia is a frequent complication of hypothermia for two major reasons: 

1) cold diuresis, which is believed to result from peripheral vasoconstriction, increased venous return, and increased ANP; 

2) catecholamine-induced shift of KCl into cells.  

Interestingly, the latter seems to depend on the type of protocol used to induce hypothermia.  Core cooling increases norephinephrine but not epinephrine, and therefore does not cause a shift of K into cells.  In contrast, external cooling (which was used in this case, with the application of cooling pads) increases epinephrine disproportionately to norepinephrine.  The B₂ agonist actions of epinephrine cause a shift of K into cells.  It is therefore critically important to avoid KCl repletion during rewarming due to the risk of rebound hyperkalemia, particularly in oliguric patients such as this one who are unable to deal with the excess potassium load once it moves back out of the cells during rewarming.

Posted by David Leaf