New potential drug targets in ADPKD

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Currently there is no good treatment for the most common
inherited cause of ESRD, adult polycystic kidney disease. There have been a
number of high profile trials in ADPKD in recent years. These trials have endeavored
to show a reduction in cyst growth and GFR decline with everolimus, sirolimus) and most recently Tolvaptan (TEMPO). The longer (2years) and larger (433 patients) of the
two mTOR inhibitor trials (everolimus) did show a significant reduction in cyst
growth at one year but not in GFR reduction. The shorter sirolimus trial failed
to show a reduction in cyst growth or GFR decline. The TEMPO trial was over 3
years, had 1445 patients and did show that the V2 antagonist Tolvaptan slowed
GFR decline (reciprocal of the serum creatinine level, −2.61 [mg per
milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; p=0.001)
and cyst growth, 2.8% per year (95% confidence interval [CI], 2.5 to 3.1),
versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0). The
jury is still out about the clinical applicability of these drugs and there
have been criticisms. For example, tolvaptan is very expensive and would need
to be used long term. In the mTOR inhibitor trials some argue doses could have
been higher and the lack of hard end points speaks for itself.
However, all is not lost. A potential new drug target in
ADPKD was reported by Rowe et al. in Nature Medicine last month. A good overview
of the topic can also be found in the same issue.
Using MEF cells from pkd-/- and pkd+/+ mouse littermates
they found that growth medium from the pkd-/- cells was more acidic and that
the pkd-/- cells had a higher ATP content. To investigate which metabolic pathways
might be causing this difference they used NMR spectroscopy and found lower
glucose and higher lactate levels in the knock out cells. They then used a
mitochondrial ATPase inhibitor to determine the source of higher ATP and found
only wt cell had a reduction in ATP with this treatment.  Then the investigators did a real-time PCR
analysis on the pkd-/- cells and found an upregulated glycolysis signature. They
thus concluded that the pkd-/- cells rely on aerobic glycolysis for their
energy demands. This is known as the Warburg effect described in cancer cells
(Otto Warburg, a physician-scientist, received the Nobel Prize in Physiology or
Medicine in 1931). To see if these in vitro findings translated into in vivo they
used Ksp-Cre; Pkd1flox/− mice, which develop early and severe PKD and measured 13C-glucose
or 13C-lactate using 13C-NMR. The findings were the same. The authors then used
2-deoxyglucose (2-DG) an analogue of glucose that is unmetabolised. They
treated wt and pkd deficient mice this compound and found that the pkd
deficient mice had a lower cyst index and lower 13C-glucose consumption as
measured using 13C-NMR.
This interesting study proposes that the use of drugs
targeting this pathway in combination with other drugs may reduce cystogenesis
and progression of CKD in ADPKD. The authors do stress that their summary with
regard to human treatments is speculative. In all I think the future is not so
gloomy for ADPKD.
Posted by Andrew Malone

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