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How do cysts grow in polycystic kidneys? How can we stop them?

May 21, 2009

There’s a lot of very interesting clinical trials going on a the moment, and most are sounding quite promising. There are 34 listed at clinicaltrials.gov! There are more than ever going on now because a breakthrough discovery was made a few years ago when researchers discovered what makes cysts grow. They examined the fluid from PKD cysts and found that it contained antidiuretic hormone vasopressin, epidermal growth factor, and a lipophilic substance which stimulates the accumulation of  cyclic adenosine monophosphate. Source: Therapuetic approaches to ADPKD.  So now we know which substances stimulate kidney cells to turn into fluid-filled cysts, and this means we can test out various pharmaceuticals and other things to see if we can stop this overabundance.

We also now know that the hypertension seen in most PKD people is probably caused by cyst growth: the idea is that growing cysts cause ischemia (impaired blood flow) inside the kidney. This makes your kidney think you’ve developed low blood pressure from low blood volume, so it releases renin, a hormone produced in the kidney, which regulates blood pressure among other things. But the rest of your body usually has normal blood flow, so your systemic blood pressure goes up.

This is important to remember when you hear about kidney disease and blood pressure. Uncontrolled hypertension can cause kidney damage for sure, but in PKD people, hypertension is more usually a sign that there is cyst growth. (Which may, in turn, cause further kidney damage, which you really want to avoid.) It’s also why antihypertensive medication that deals with renin seems to work best in those with PKD. Beta blockers aren’t usually recommended in PKD, but calcium channel blockers may be used if the others don’t work well. The PKD Foundation has a good page with information about hypertension in PKD. [Edit:  Commenter Kyle has pointed out that beta blockers can in fact act on renin, and may be used in PKD. See the comments for my reasons why I’d come to think they were less useful in PKD.]

So what are some of the main clincial trials using this information? After quite a few trials on rats and mice which showed very promising results for various therapies, human trials are underway. Many people with PKD will have heard of the PKD-HALT study, which is seeing if using two types of anti-hypertensives which act on the renin-angiotensin system will help slow the progression of cyst growth. There’s also the TEMPO 3/4 study which is trialling Tolvaptan, a substance that blocks the vasopressin from ‘sticking’ to the vasopressin receptors. There’s also a trial which is attempting to mimic the diuretic effect of Tolvaptan with consumption of large volumes of water. Another trial is testing if rapamycin/Sirolimus will stop cell proliferation in PKD. Also showing promise are trials of PLX5568 (a drug which hasn’t been named yet); it’s a new protein kinase inhibitor shown to stop cyst growth and reduce kidney volume in animal trials.

Sounds good to me.

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4 Comments leave one →
  1. May 21, 2009 9:21 pm

    Hopefully this article will drive home the importance of taking BP meds!

    • pkdnews permalink*
      May 21, 2009 9:55 pm

      Definitely, Richie! While in the general population doctors don’t usually start medicating until your BP reaches 140/90, I know some nephrologists recommend PKD people take them if BP rises above their normal level at all, and try to get it down under 120/70.

  2. Kyle Elwood permalink
    May 25, 2009 8:38 am

    The following comment which you made confuses me: You stated…”It’s also why antihypertensive medication that deals with renin seems to work best in those with PKD (very true). Beta blockers aren’t usually recommended in PKD” (where did you see this mentioned?)

    Since “stimulation of β1 receptors on the kidney causes renin release,” it should be anticipated that beta blockers which have beta 1 receptor blocking action should reduce renin release from the kidneys…which they do. “Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone system with a resultant decrease in blood pressure due to decreased sodium and water retention” and reduced vasoconstriction.

    As such, beta blockers do have a positive effect on the renin-angiotensin-aldosterone system (RAAS) in regards to the treatment of hypertension,
    and as such, are useful in treating hypertension (and MVP) in PKD patients.

    Those beta blockers which also have α1-Receptor antagonism “(e.g. labetalol and carvedilol) exhibit mixed antagonism of both β- and α1-adrenergic receptors, which provides additional arteriolar vasodilating action.” These beta blockers do not reduce renal perfusion like some older generation beta blockers can do, so they are very appropriate for the treatment of PKD. In addition, since 25% of PKD patients also have mitral valve prolapse (MVP) and this condition often demonstrates itself with palpitations and racing heart, beta blockers prove very useful in reducing or eliminating these cardiac impacts while at the same time reducing blood pressure.

    I use low dose carvedilol (with two other anti-hypertensives) and it helped reduce my blood pressure and essentially stopped my palpitations and racing heart problems, as well.

    • PKDnotes permalink*
      May 26, 2009 10:09 am

      Hi Kyle – I based my information on what I’d seen published primarily at the PKD Foundation’s site; and from what I hear most nephrologists prefer ARBs or ACEII inhibitors because that’s what the most recent studies have been using. I can’t really comment on anti-hypertensive usage in the USA but I know that in Australia and most of Europe, people with kidney disease including PKD are routinely given ARB/ACEIIi preferentially over beta blockers because of belief that they are more effective for most people than beta blockers. BBs are also contraindicated in people with asthma, and Australia and New Zealand have amongst the highest incidence of asthma in the world (including me), more than double the rate in the USA, so they’re less popular with doctors here. Taking a cue from your comment, I just found an article in one of the medical journals which suggests that BBs could be useful in PKD, but no studies have yet been conducted. It would definitely be interesting to see. I’ll certainly amend my post to note what you’ve said, though, useful to know. Thanks for the information!

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