First patient data on sirolimus for ADPKD

UPDATE: please see this post with newer, more definitive data.

Initial patient visits for autosomal dominant polycystic kidney disease are different from just about any other patient visits. It is the only disease in which I spend a significant amount of time discussing the areas of bleeding edge research that have promise but are not yet available. I tell my patients about three current research thrusts:

  1. Combination ACEi-ARB
  2. ADH-antagonists
  3. mTOR inhibitors
I spend time doing this because the hardest thing for patients to accept with a new diagnosis of ADPKD is the twin truths of the disease: 1) the inevitability of the disease and 2) the lack of any effective intervention that can meaningfully make a difference. Most of the patients referred to me have a fair bit of knowledge about the disease. They have seen their siblings, a parent and a fair number of cousins, uncles and aunts go through dialysis, transplant and the other rigors of kidney failure. Everyone wants to know what they can do to reduce the progression, what can they do to avoid their genetic destiny. Tragically, I feel like a medical Cassandra because there is little I can do to intervene so I am left to weave tales of a happier tomorrow.
Well, tomorrow has gotten a little closer with the publishing of the first human study of mTOR inhibitors in ADPKD.

Polycystic kidney disease cells show abnormal activation of the Ser/Thr kinase target of of rapamycin. This enzyme coordinates cell growth and proliferation. In three animal models of PKD, there is evidence of inappropriate activation of mTOR in the renal cysts. Because of this, blocking mTOR with rapamycin (same thing as sirolimus) is one of the most promising research avenues in ADPKD. 

Up to now most of the data has depended on animal studies. Though there have been some retrospective analysis in humans with ADPKD who received a kidney transplant with sirolimus as part of their immunosupression. On average investigators found a 24% reduction in kidney volume with sirolimus compared to an 8% reduction with alternative agents (ref). Similar improvements in liver cysts were found, 12% reduction with sirolimus versus 14% increase without (ref).

In this latest study by Perica et al. they had 21 patients and they received either conventional therapy or sirolimus (initial dose: 3 mg daily) for six months and then each patient crossed over to the opposite arm, so every patient received both control and experimental therapy. Six patients dropped out for various reasons and the researchers ultimatly reduced their target sirolimus levels from 10-15 ng/ml to 5-10 ng/ml. The authors explained the adverse reactions in the discussion:

Three patients were prematurely withdrawn from the study because of the onset of an erythema nodosus in one case and thrombocytopenia in two cases after a few days of sirolimus therapy, when sirolimus dosage was titrated to target trough levels between 10 and 15 ng/ml (all events fully resolved with treatment withdrawal). The poor tolerability of this high-dosage regimen led us to reduce the target levels to 5 to 10 ng/ml. With this approach, no serious event requiring treatment interruption was observed.

The primary outcome was change in the kidney volume. The authors, additionally, looked at changes in cyst volume and renal parenchymal volume which was important as they found an increase in the renal parenchyma with stable cyst volume during sirolimus and a reduction in renal parenchyma and increase in cyst volume during usual care.

The primary outcome, a change in renal volume was not significant, P=0.45; however, cyst volume increased more on conventional therapy, P=0.013 and parenchymal volume increased more on sirolimus, P=0.005.

I know that the EBM snobs will turn their noses up at these secondary end-points but in a small pilot study I feel this shows real promise. It also indicates, to me, that total kidney volume might not be the best intermediate end point for ADPKD. It looks like sirolimus causes non-functioning cysts to be replaced with viable renal parenchyma, and it seems unfair to punished the drug for that but using total kidney volume as opposed to cyst volume does just that.
The authors then try to establish some dosing guidelines but this is probably a fool’s errand to run with only 15 people completing the protocol. Regardless of its validity they come to 0.049 mg/kg as the optimal dose (3.5 mg per day for a 70 kg male).
The authors had an interesting angle on some of the more common side effects associated with sirolimus:

Hypercholesterolemia is another widely known adverse effect of mTOR inhibitors. Our data, however, show that in patients without concomitant medications that may also ad- versely affect the lipid profile, such as steroids or calcineurin inhibitors, hypercholesterolemia is mild and can be easily managed just with dietary counseling. Thus, this adverse effect does not seem to be a major drawback of sirolimus therapy, even in the case of prolonged exposure.

The frustration of ADPKD comes from the inevitability paired with our medical impotence. Every year at our conferences we are shown western blots and animal models that hint at a new day. I believe the first rays of that new day are poking over the horizon.

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