Therapeutics in post-surgical AKI
Jonathan Himmelfarb, MD (University of Washington)
In our last blog for the 2012 NKF meetings, Dr. Himmelfarb gave a fantastic lecture on the therapies available for treating AKI. In short, there are no FDA-approved drugs to hasten renal recovery. You could stop reading at this point, but I’d advise that you continue because Dr. Himmelfarb provided some excellent information regarding 1) atrial natriuretic peptide (ANP), and 2) remote ischemic preconditioning.
ANP was first identified in the late 1970’s by Dr. deBold. He took the hearts of rats, separated the atria and ventricles, ground up both of them, then injected the ground atria into one set of rats, ground ventricles in the other. He noted that those rats with the atria injected had a brisk and larger natriuresis than the ventricle-injected rats. Interestingly, and of note to young physician-scientists, his paper was rejected by every journal. In the end, the paper was published in an obscure journal, Life Sciences, in 1981. Not discouraged, he continued his research and in 1985, published a paper in Science. Well, lo-and-behold the original paper in Life Sciences was cited by the 1985 Science paper, and his original article became one of the greatest cited papers in all of medical science (in an obscure journal).
There was much promise and hope with ANP. Phase 1 and 2 trials were all positive. Unfortunately, every phase 3 clinical trial has been negative. Dr. Himmelfarb mentioned one negative trial in particular (NEJM 1997). Though it showed negative results (i.e., ANP versus placebo showed no difference in dialysis-free survival), the trial was underpowered, had a heterogeneous population, and entered patients late in their disease (eGFRs from 3-12). Newer studies are small in number but are showing some promise for ANP. We know need larger powered studies to determine, once and for all, if ANP has a role in treating AKI.
Next is remote ischemic preconditioning (RIP)(Lancet 2009 p. 1557). This is a very interesting therapy, as it has nothing to do with developing a molecule. The idea is that the body has its own defense mechanisms against ischemia to keep target-organs safe. Thus, one should iatrogenically induce ischemia (e.g., a limb), allowing these unknown ischemia-protective molecules to be released into the systemic circulation. Once this is done, surgery can be scheduled knowing that these protective molecules are in the circulation, protecting vital organs just prior to the surgery.
Remote ischemic preconditioning is under investigation but early data (though underpowered) is showing some promise.
Stay tuned for more info about ANP and RIP