Monday, December 20, 2010


Tenofovir can cause proximal tubular damage? Recent data show it to damage what part of the cell?

Nucleas 2%

Mitochondria 71%

MRP-2 Channel 17%

NK ATPase pump 7%

The HIV drug Tenofovir, as we all know , can be nephrotoxic. Proximal tubular damage is what we usually see with full blown Fanconi syndrome as well in some cases.  What the organic anion drug do in the proximal tubule cell?  It is delivered to the basolateral membrane of the proximal tubule cell and its transported into the cell by the organic anion transporter OAT-1.  Once it enters the cell, the drug is secreted into the urinary space via MRP-2 and MRP-4 ( multidrug resistance protein transporters).  The damage we see with this drug is via direct mitochondrial DNA depletion and damage done by the drug within the cell.  Disturbances in the secretory pathway ( increased OAT-1 or decreased MRP efflux) can lead to increased drug levels in the cell and ultimate mitochondrial damage.  MRP-2 is a good answer but mitochondria is the best answer as the damage really is via mitrocondria that leads to the final proximal cell tubulopathy. 
This has been shown in EM findings or ultrastructual findings that show eisonophilic intracytoplasmic inclusions within the proximal tubular epithelial cells, that are the giant mitochondria seen usually.  The mitochondria have abnormal cristae and hence don't function.  
This ultimately leads to strange shaped and large shaped mitochondria that are non functional and tenofovir induced toxicity. 
A nice reference from KI is listed below:

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