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Renal and Extrarenal Complications of ADPKD: Facilitating Better Patient Care

  • Authors: Benjamin D. Cowley, Jr, MD; Arlene B. Chapman, MD; Charles Edelstein, MD, PhD
  • CME Released: 10/2/2013
  • Valid for credit through: 10/2/2014, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for nephrologists, cardiologists, and primary care physicians.

The goal of this activity is to provide expert perspectives to help physicians provide optimal care for their patients with autosomal-dominant polycystic kidney disease (ADPKD). This roundtable discussion will examine the current landscape as it pertains to the current understanding of ADPKD, its clinical manifestations and complications, and treatments options.

Upon completion of this activity, participants will be able to:

  1. Apply current approaches for identifying individuals with ADPKD
  2. Identify available approaches to treatment and monitoring of disease progression, including renal and extrarenal complications of ADPKD


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  • Benjamin D. Cowley, Jr, MD

    Section Chief of Nephrology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma


    Disclosure: Benjamin D. Cowley, Jr, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Otsuka Pharmaceutical Co., Ltd.

    Dr Cowley does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Cowley does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Arlene B. Chapman, MD

    Professor of Renal Medicine, Emory University School of Medicine, Atlanta, Georgia


    The opinions expressed are those of Dr Chapman and do not necessarily reflect the views of Emory University or Emory Healthcare. Dr Chapman’s participation in this activity does not constitute or imply endorsement by Emory University or Emory Healthcare.

    Disclosure: Arlene B. Chapman, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Otsuka Pharmaceutical Co., Ltd.; Pfizer Inc; Sanofi
    Received grants for clinical research from: Otsuka Pharmaceuticals

    Dr Chapman does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Chapman does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Charles Edelstein, MD, PhD

    Professor of Medicine, Division of Renal Diseases, University of Colorado, Denver, Colorado


    Disclosure: Charles Edelstein, MD, PhD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AbbVie Inc.; Cordis Corporation
    Served as a speaker or a member of a speakers bureau for: National Kidney Foundation
    Received grants for clinical research from: Wyeth Pharmaceuticals Inc.

    Dr Edelstein does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Edelstein does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Anne G. Le, PharmD, RPh

    Lead Scientific Director, Medscape, LLC


    Disclosure: Anne G. Le, PharmD, RPh, has disclosed no relevant financial relationships.

CME Reviewer

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

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Renal and Extrarenal Complications of ADPKD: Facilitating Better Patient Care

Authors: Benjamin D. Cowley, Jr, MD; Arlene B. Chapman, MD; Charles Edelstein, MD, PhDFaculty and Disclosures

CME Released: 10/2/2013

Valid for credit through: 10/2/2014, 11:59 PM EST


Welcome and Introduction to ADPKD

  • Benjamin D. Cowley, MD: Hello. I am Dr Ben Cowley, chief of nephrology and hypertension at the University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma. I would like to welcome all of you to this program titled "Renal and Extrarenal Complications of Autosomal Dominant Polycystic Kidney Disease (ADPKD): Facilitating Better Patient Care."

  • Slide 1.

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  • Joining me today is Dr Arlene Chapman, professor of medicine in the division of nephrology at Emory University School of Medicine in Atlanta, Georgia. Welcome, Arlene.

    Arlene B. Chapman, MD: Thank you for having me.

    Dr Cowley: And Dr Charles Edelstein, professor of medicine in the division of nephrology at the University of Colorado in Denver at Aurora, Colorado. Welcome, Charles.

    Charles Edelstein, MD, PhD, FAHA: Thank you.

    Dr Cowley: Before we begin, I would like to note that this program will discuss investigational drugs, mechanical devices, biologics, or diagnostics that are not approved by the US Food and Drug Administration (FDA) for use in the United States.

  • Slide 2.

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  • Our goals today are to apply current approaches for identifying individuals with ADPKD and to identify available approaches for treatment and monitoring of disease progression including renal and extrarenal complications of ADPKD.

  • Slide 3.

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  • To start our discussion, I would like to spend just a few minutes providing a brief clinical introduction to ADPKD, and I apologize to Dr Chapman and Dr Edelstein since you already know all this, but feel free to chime in as I go through this brief overview.

    ADPKD, as the name implies, requires only 1 abnormal gene for the disease to be manifest. At least 2 different genes, when modified, can cause ADPKD. The PKD1 gene, which is located on chromosome 16, codes the protein called polycystin 1, accounts for approximately 85% of cases, and seems to cause a more aggressive form of the disease. The PKD2 gene is located on chromosome 4 and encodes the protein called polycystin 2, which accounts for approximately 15% of cases and seems to cause a somewhat less severe form of the disease.[1]

    There are a few families of patients with PKD who do not have genetic markers for PKD1 or PKD2, although the vast majority do, so it is possible that there are other genes that, when mutated, can cause PKD.

    We are not certain what the functions of the polycystins are, but we do know the sequences of the proteins, and Dr Chapman will more about that. It is thought that polycystin 1 may have a role in signal transduction. It does have multiple transmembrane-spanning domains and intracellular regions, which suggests that it may have a role in signal transduction and extracellular domains, which in turn indicates that it may have a role in cell-cell and cell-matrix interactions. Polycystin 2 is thought to act as a cation channel with permeability for calcium, and there is some thought that polycystin 1 may actually regulate the function of polycystin 2.[1]

  • Slide 4.

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  • ADPKD is extremely common. From autopsy studies, the prevalence is thought to be somewhere between 1 in 400 and 1 in 1000 live births.[2] What this means is that between 300,000 and 750,000 individuals in the United States are thought to be affected by this disease, and millions are affected worldwide. However, only about 200,000 cases have been diagnosed in the United States, and this is important because it has given PKD the status of an orphan disease. As with many dominantly inherited diseases, between 5% and 10% of cases are thought to arise from new mutation, so there is no family history.

  • Slide 5.

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  • Though it is called PKD, it is actually a multi-organ disease.[2] Essentially, 100% of individuals with 1 of these mutated genes will develop enlarged kidneys. About 50% will develop renal failure, which typically occurs between 40 and 60 years of age. Hypertension is common, occurring in as many as 50% of patients in their younger years and, as they develop renal dysfunction, essentially in 100% of cases. Liver cysts are seen in the vast majority of cases and seem to increase in frequency with age. Cardiac valvular abnormalities, particularly mitral valve prolapse, occur in about 25% of patients. Arterial aneurysms involving both large and small vessels, including the cerebral circulation, can be seen, and we will try to discuss screening for these if we have time. There is an increased frequency of gastrointestinal (GI) diverticula and you can see cysts in other organs such as the pancreas and arachnoid villi, which are typically of no clinical significance.

    Dr Edelstein: Ben, do you think liver cysts are more common in females than males?

    Dr Cowley: Probably; they certainly seem to be more aggressive in females, and I think both of you are well aware that there is evidence to suggest that women who have multiple pregnancies who take hormone replacement therapy have more aggressive cysts, so we should think twice about prescribing it.

  • Slide 6.

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Genetic, Molecular, and Cellular Mechanisms of PKD

  • Arlene, I think you want to present some data about diagnostic approaches and other information, so I will turn this over to you.

    Dr Chapman: Sure. Thanks, Ben.

    ADPKD truly is a systemic disease involving the kidneys, liver, pancreas, spleen, and brain. It is hereditary, so even though you may think of it as an adult disease it starts in utero. ADPKD starts out as small sacs in the kidney tubules that are present close to or around the time of birth.[3] As you heard, there are 2 genes responsible for PKD, PKD1 and PKD2, and even when we see patients in the clinic, we cannot tell who is a PKD1 and who a PKD2 patient. Their phenotypes are identical. As a population, they actually manifest different levels of severity, and PKD2 patients usually start dialysis almost 20 years later than their PKD1 counterparts. We now know that this is related both to the size of their kidneys and the number of cysts they have, which is much lower in the PKD2 patient population.

  • Slide 7.

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  • This is the kidney disease mechanism: There is a mutation that leads to an abnormal protein; the protein then affects cell function, meaning proliferation, fluid secretion, and cell-cell crosstalk that turns into a cyst; these cysts depart from their nephron; get larger and larger; grow on their own; and basically replace the kidney with cysts.[4]

    Dr Cowley: Speaking of cysts, since you probably know more than just about anybody about kidney size, I am guessing that is probably something you want to talk about.

  • Slide 8.

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  • Dr Chapman: Sure. I wanted to talk a little about how we diagnose PKD, particularly since there are a number of other cystic diseases and we need to know what the cyst burden is and how to measure it. We actually have reliable ways of measuring this now in patients with PKD.

    ADPKD accounts for over 90% of all cystic diseases, and there are about 15 or 16 different hereditary cystic diseases of the kidney. If we just rely on cyst presence to diagnose PKD, it will be difficult to differentiate them. There is recessive polycystic kidney disease (RPKD), tuberous sclerosis complex (TSC), von Hippel-Lindau, medullary cystic kidney disease (MCKD), familial juvenile nephronophthisis (FJN), and others, such as glomerulocystic kidney disease (GCKD). They all have cysts, so if we just count on cyst number to make a diagnosis we will probably be mistaken a number of the times.

    What we do know now is that kidneys get larger in PKD and the cyst burden is manifest by an increase in kidney size; we do not see this in any other cystic diseases of the kidney. We may see it in the recessive form of PKD, which occurs at birth, is really rare, and usually results in renal failure by the time a patient is somewhere in their teens. Also, the increase in kidney size actually disappears quickly after birth. PKD is the only disease where cysts grow and grow and grow over decades, resulting in kidneys that can weigh 20 to 30 times what a normal kidney weighs.

  • Slide 9.

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  • We can actually measure this quite well now using standard known radiologic techniques: magnetic resonance imaging (MRI), computed tomography (CT), or ultrasound.[5]

  • Slide 10.

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  • If we look at different diseases, there is cyst distribution all throughout the kidney. Sometimes it is restricted to the medulla; sometimes to the cortex. In many cystic diseases the cysts are tiny, but they are associated with interstitial fibrosis, and those are the kidneys that are cystic but actually relatively small. In PKD, not only are these cysts distributed throughout the entire kidney, in the medullary and cortex, they are extremely large and you do not see that in any other kidney disease except perhaps tuberous sclerosis. Kidney enlargement is invariably present in PKD and is an important feature to keep in mind if you are not sure about the diagnosis of PKD.

    As you mentioned, Ben, 10% to 15% of people do not have a family history of PKD and so you do see patients with that genetically-dominant disorder coming into the doctor’s office. So to find out if that patient really has ADPKD you need radiologic evidence. For the most part we can do this with ultrasound. Ultrasound is incredibly reliable.

    Usually by the time a patient is 30 years of age they will have cysts in their kidneys.

  • Slide 11.

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  • If a patient comes into the office knowing that they have a family history of PKD, we only need 3 unilateral or bilateral cysts to be present if they are younger than 40 years of age to make the diagnosis. If they are older, because simple cysts develop in the general population and can confuse the picture, more cysts, usually 4 must be present bilaterally to make a diagnosis. If a patient is older than 60 years of age and they come in for a diagnosis -- which is pretty unusual because most people are diagnosed by the time they are 30 years of age -- they have to have at least 8 cysts present bilaterally.[6]

    We use ultrasound to diagnose ADPKD. It is noninvasive, inexpensive, and readily available. Ultrasound can detect cysts as small as about half a centimeter in diameter. Sometimes, when patients want to donate a kidney to a family member and want to make sure that they do not have PKD, we might use a higher resolution imaging study such as MRI or CT because we can really see cysts as small as 1 mm in diameter, so the less than 5% of cysts we may miss on ultrasound will be seen with these imaging techniques.

    Dr Edelstein: With those criteria, when patients who are older than 50 years of age present to our clinic with chronic kidney disease (CKD), we do a routine ultrasound and we see cysts. And we say okay, you have a new diagnosis of PKD and this is the cause of your mild CKD and hypertension. It does happen.

    Dr Chapman: Yes, but those kidneys are not large. They have actually shrunk a little, probably due to reduced blood flow to the kidneys, so in that case kidney size becomes a helpful confirmatory diagnostic tool. You do not see PKD patients with stage 3 CKD and normal-sized kidneys. There are a number of population reports that reported patients without any hereditary predisposition and between 4 and 8 cysts, the number that we need to see to diagnose PKD. In those patients, the cyst size is predominantly less than a centimeter, which means we can also assume that cyst size is typically greater than a centimeter when in an individual comes in for diagnosis with ADPKD.[7]

  • Slide 12.

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  • We have a number of clues to help identify the standard presentation of PKD.[8] Over 95% of PKD1 patients have kidney cysts by the time they are 30 years of age. The liver indications are a huge signpost in terms of diagnosis because there is no other cystic kidney disease that has cysts in the liver, and more than 80% of patients will have cysts in the liver by the time they are 30 years of age. Intracranial aneurysms will be present in 5% to 8% of PKD patients, which is a big concern for patients. If we have time, we should address that today. High blood pressure occurs early in the majority of patients before they lose kidney function, so it is not unusual to actually discover PKD in a patient on routine screening for hypertension. Proteinuria is part of many kidney diseases, although it is not actually common. However, along with kidney size, it is important prognostically. If it is present, although usually it is less than 1 g a day, it means the patient is going to have worsening kidney function.

    Dr Edelstein: What about hematuria? What percentage of patients with PKD do you think have hematuria independent of stones or another source?

    Dr Chapman: Do you mean hematuria from a cyst rupture or for whatever other reason? About 40% of patients with PKD will have had an episode of blood in their urine by the time they are 30 years of age, well before they have lost any kidney function.

    Dr Edelstein: What about microscopic persistent hematuria?

    Dr Chapman: Yes. That is a tough one because you have to rely on screening to reveal it. Patients will always remember when they see blood in the urine but they may not remember if and when they were told by their doctor that they have microscopic hematuria, so it is a little harder to track. We certainly know that visible blood in the urine, or gross hematuria, is present in about 40% of patients by the time they are 30 years of age, and kidney stones are present in about 16% of patients. The most bothersome symptom for most of these patients, quite frankly, is pain, which is related to the size of their kidneys. More than 80% of patients will have had an episode of pain that they can recall within the last 3 months by the time they are 25 to 30 years of age.

    This is a disease that has a lot of symptoms that impact people’s lives. They probably have not had renal insufficiency yet, because that typically develops much later once their kidneys have gotten to be such a size that they are progressing to renal failure. There is just no reserve left in the kidneys, which are enlarged and filled with cysts.

  • Slide 13.

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  • We know now that kidney volume increases at a predictable rate and each individual has their own exponential rate of kidney growth, and we can actually predict a patient's kidney volume because of this. We can take only one measurement of their current kidney volume and what a normal adult kidney size is can reliably predict what their kidney volume was at a certain age. On average, kidney volume grows about 5% per year, equivalent to about 80 mL, or half a kidney a year. This is easy to measure with MRI, so we can determine easily and quickly whether or not we stopped or reversed cyst growth.

    We also know that all the symptoms that we just talked about, such as blood in the urine, high blood pressure, and pain, all seem to correlate with a certain kidney size. Once a patient has about 3 or 4 times the normal kidney volume, hypertension starts to kick in, way before they lose kidney function. People are starting to develop pain around that time and gross hematuria occurs just a little later when the cysts are large enough to spontaneously rupture. We can predict the disease course, to a point, based on these symptoms because we know how much they are related to kidney size.

    Kidney size is not only important for diagnosis, it is important for predicting patient prognosis. We can tell patients that they probably will not end up in renal failure if their kidneys are small and they are in their 40s or 50s. For many patients, knowing that renal failure is not going to happen as it did to other family members is a huge relief. I think we have come a long way by using kidney volume to help manage our patients.

    Dr Edelstein: How do we do that in the clinic? You just look at the size of the kidney? If your kidney measures 13 centimeters, that is not too big. What if it is 20 centimeters? Some studies provide a 3-D image of the kidneys, so in general, how do you use ultrasound to get an idea of the patient’s kidney size?

    Dr. Chapman: Normal kidney length is about 10 to 12 cm in men and about 11 cm in women. Kidney length correlates pretty well with a patient’s height. Shorter people tend to have shorter kidneys and taller people tend to have longer kidneys. We know based on ultrasound measurements done in addition to MRI measurements that when kidneys reach about 16 to 17 cm in length the patient is getting to the point where all the secondary problems (hypertension, blood in the urine, and probably the future development of CKD stage 3) are going to develop.

    Kidney volume, though, is a much more accurate assessment of cyst burden. This is not something that is done regularly done today, but it is an extremely valuable measurement. We do not ask the radiologist to obtain volume measurements. It is doable, but it takes some time and they need the right type of software for their scanners to be able to put a volume estimate together.

    I think kidney volume is really the best way of assessing disease severity right now, and it is really independent of genotype. PKD2 patients typically have smaller kidneys, which might explain why they start dialysis about 15 to 20 years later and have fewer cysts than PKD1 patients. However, when examining kidney volume some PKD2 patients' kidneys are actually pretty large and they behave like an individual with PKD1. On the other hand, some PKD1 patients have relatively small kidneys, probably related to the type of mutation they have, and they actually do quite well. It is kidney size more than anything else, more than hypertension, proteinuria, or genotype, that really predicts how well patients with PKD are going to do.

    Dr Cowley: Let's pause for a moment and let the audience weigh in on these questions that we are going to present to you.

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Treating the Complications of ADPKD

  • Now that you have had a chance to look at those questions, I just want to quickly review the complications associated with PKD because I wanted to give Dr Edelstein plenty of time to talk about future therapies.

    Dr Chapman mentioned most of these complications, so I will just review them quickly. Complications in PKD run the gamut from mundane to severe. Something as simple as the inability to concentrate your urine because of the distortion of the kidneys will lead to nocturia.[2] We need to make sure these patients stay well hydrated. Pain can be a significant problem and merits its own discussion. Bleeding is usually self-limited if you put the patient on bed rest and give them fluids, although sometimes more aggressive intervention is required. Infections are a particular problem, especially if they develop within a cyst because you have to use antibiotics that penetrate cyst cavities and are effective against the usual organisms. Typically, fluoroquinolones are the first-line agents, although sometimes we use other agents.

    As we discussed, hypertension is a particular issue and we will talk more about that in just a moment. Aneurysms in the cerebral circulation are a concern, and we typically screen people with a family history of a brain hemorrhage or stroke if they have new onset of headaches, worsening of pre-existing headaches, or are in a high-risk occupation (eg, airline pilot). Kidney stones are seen about twice as often as in the general population. Obviously, you want to make sure patients keep their urine diluted and try to avoid things that will lead to infection. If they have kidney stones, they are generally good candidates for urologic interventions and a metabolic stone evaluation is certainly appropriate.

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  • Arlene already talked about some of the risk factors for renal function deterioration.[2] Unfortunately, we do not have one great test that will tell you whether or not a patient is going to have renal failure. Some things certainly make it more likely, such as larger kidneys; younger age at diagnosis; hypertension, especially in young patients; protein or gross blood in the urine; male gender; more than 3 pregnancies in women; the PKD1 mutation; and smoking.

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  • The clinical characteristics[2] we should monitor are relatively straightforward, I think, although I would certainly be interested in the panel’s thoughts on this. Certainly, we need to monitor and treat blood pressure problems. Routine urinalysis to look for proteinuria and hematuria and protein quantitation is reasonable. Serum lipids, because there is some evidence in animals that lipid-lowering agents may be of benefit,[9] and obviously, serum creatinine and estimated glomerular filtration rate (eGFR) should be obtained. Whether kidney size should be monitored routinely is unclear, because although it can help us predict future deterioration of function, it does not necessarily change treatment. Obviously, when patients develop renal dysfunction, we need to monitor the usual CKD parameters and treat those accordingly.

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  • Unfortunately, one of the dirty little secrets of those of us who see a lot of patients with PKD is that today there is no approved specific treatment to slow disease progression. There are a number of things that people generally need to do as we just discussed: appropriate blood pressure control and generous water intake to decrease the risk of stones. Generous water intake may slow disease progression because it is thought that cyclic adenosine monophosphate AMP (cAMP) has a strong effect on PKD progression in the kidney.[10] Cyclic AMP is mainly generated in response to vasopressin, so drinking a lot of water can potentially suppress vasopressin and decrease renal cAMP levels.

    Dr Edelstein: I will talk about that as a novel therapy, although there are not a lot of studies of using water for the treatment of disease.

    Dr Cowley: Obviously, we want to at least tell our patients to stop smoking. There are a few other things that seem reasonable, although little data are available. Caffeine can potentially make cAMP last longer, so I tell people to avoid caffeine. As I mentioned, there are some data from animals with PKD that suggest that statins slow disease progression,[9] but we have no data in humans. I do not think giving every patient with PKD a statin is justified, but I will certainly check their lipid levels to see if there is a reason to do so.

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  • Hypertension probably deserves at least a brief special mention because there is a large trial going on looking at hypertension and PKD. It is thought that agents that block the renin-angiotensin system are probably of some special benefit in PKD.[11] The Halt Progression of Polycystic Kidney Disease (HALT PKD) trial[12] is evaluating angiotensin-converting-enzyme (ACE) inhibitors in comparison to combination therapy with an ACE inhibitor and an angiotensin receptor blocker (ARB), using 2 different blood pressure targets. Hopefully, within the next couple of years we will have that data and be able to answer some of these questions.

    I do get the question about the use of calcium channel blockers on a fairly regular basis. There are data from animals with PKD that suggest that calcium channel blockers actually worsen disease progression.[13] There are no data in people to support this yet, and so I do not think we can make a blanket statement that we should not use them in humans with PKD. They are typically not my first choice and I do not know how you guys feel about that, but I do not recommend them. They are such good antihypertensive agents, though. If you cannot control a patient’s hypertension otherwise, I use them, but they are not my first choice.

    Dr Edelstein: What is your second choice after an ACE inhibitor or an ARB? Some people believe that diuretics rev up the renin-angiotensin system so calcium channel blockers have an effect.

    Dr Cowley: I think that is difficult to answer. In a patient with CKD, I think it is difficult to control their blood pressure without a diuretic, and so it is a bit of a quandary. If they do not have CKD you can use beta blockers. I do not think beta blockers alone are good antihypertensive agents but combination alpha-beta blockers, I think, are pretty decent.

    Dr Chapman: Beta blockers inhibit the renin-angiotensin system.

    Dr Cowley: Correct. Alpha blockers are okay. Centrally-acting agents are okay. I do not think we have a good answer. We think ACE inhibitors and ARBs are probably better, and we think calcium channel blockers might be problematic and anything else is a question of betting on the best choice.

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  • I do want to come back to the fact that there is no approved therapy for treating ADPKD. Occasionally, the issue of screening comes up and, as Arlene described, we can usually confirm a diagnosis of PKD. In the United States that may or may not be a good thing, because it can impair a patient's ability to get health insurance. That may change, but it certainly can affect a patient's ability to get life insurance, disability insurance, and maybe even a job. The question of whether or not we should be screening patients is still unanswered. I think when we have therapy for PKD things will change, because once we have potential therapy, we will want to give it to patients who have a confirmed diagnosis.

    With that as a prelude, I would like to give Charles the opportunity to talk about future therapies, and I do say when and not if. Charles?

  • Slide 20.

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Treatment Targets in PKD

  • Dr Edelstein: It is, as you know, it is an exciting time in PKD because we have some potential therapies on the horizon and more than 10 clinical trials testing the effect of various agents on cyst growth in PKD. I think in order to understand novel therapies for PKD, I would like to go over the pathogenesis of cyst formation and some of the targets in PKD.[14]

    What happens is, as Arlene mentioned, the cells lining the cysts abnormally secrete fluid into the lumen. There is also increased proliferation of the cells lining the cysts. These 2 processes can be mediated by cAMP. The fluid secretion is also mediated by the cystic fibrosis transmembrane conductance receptor (CFTR), which is chloride-driven and pumps fluid into the cells. The increased proliferation is mediated by cAMP and by the mammalian target of rapamycin (mTOR) complex. The renin-angiotensin system is also pro-proliferative, and tyrosine kinases like the epidermal growth factor receptor on these cells also mediate increased proliferation.

    The increased cell proliferation is accompanied by increased cell death, also known as programmed cell death or apoptosis. Apoptosis is mediated by a group of cysteine proteases called caspases and another group of molecules called cyclin-dependent kinases (CDK). The problem starts in the cilia. The cilia is where the polycystin-1 and -2 gene products are localized, and there is also abnormal calcium influx into the cilia.

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  • The treatment targets and novel therapies being studied are based on dealing with these abnormal mechanisms.[14] For example, the abnormal fluid secretion can be reduced with vasopressin V2-receptor antagonists. For the CFTR-induced chloride-driven fluid secretion into the cysts, studies have shown that metformin, a drug that commonly used for diabetes, and another group of diabetes drugs, the PPAR- γ agonists, can actually decrease CFTR-driven fluid secretions into the cysts. There have been positive studies in animals with vasopressin V2-receptor antagonists, the mTOR inhibitors, the ACE inhibitors, ARBs, statins, tyrosine kinase inhibitors, and epidermal growth factor receptor (EGFR) inhibitors, in decreasing proliferation. Another drug or compound that has been tested is curcumin*, which is a derivative of the Indian spice turmeric, and there is a positive study in PKD1 knockout mice that shows it reduces cyst growth. The increased apoptosis of the cells lining the cysts can be mediated by CDK, and there is a study that has found that roscovitine,* a CDK inhibitor, can reduce cyst growth in animals.

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  • I just want to touch on some of these novel therapies in a little more detail. As we mentioned before, one of the novel therapies is drinking a lot of water. It is not that we are desperate to find a therapy. it just turns out that water is a therapy for ADPKD because it causes a physiological suppression of vasopressin. Vasopressin stimulates cAMP, which stimulates proliferation. There have been positive studies in rats[15] and there is a human study that is recruiting patients now.[16]

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  • Dr.Edelstein: Other potential therapies include the somatostatin analogs octreotide and lanreotide, which inhibit vasopressin-induced cAMP, which stimulates proliferation. There have been positive studies in mice and in humans, with ongoing participant recruitment. Vasopressin V2-receptor antagonists inhibit cAMP-dependent secretion of fluid and proliferation. There have been many positive studies in animals, with ongoing and active phase I and II studies in humans. The first positive study of a drug that slowed cyst formation in humans is the study with tolvaptan which was published in New England Journal of Medicine.[17] Editor's Note: In August, 2013, the US FDA's Cardiovascular and Renal Drugs Advisory Committee voted against recommending approval of tolvaptan to treat ADPKD. A complete response letter from the US FDA was sent to Otsuka on August 29, 2013 requesting additional efficacy and safety data of tolvaptan in patients with ADPKD.[18]

    The mTOR inhibitors are another group of drugs that has caused a lot of excitement. Animal studies were strongly positive with rapamycin.[19] Unfortunately, 2 studies published in TheNew England Journal of Medicine of rapamycin and everolimus were essentially negative,[20,21] but there are still ongoing studies evaluating mTOR inhibitors that are recruiting patients.[22] ACE inhibitors and ARBs suppress the activation of the renin-angiotensin-aldosterone system in PKD, and are also anti-proliferative. There have been positive studies in rats, and the HALT PKD study, as mentioned before, is evaluating the effect of ACE inhibitors or ARBs and the combination of the two in PKD.[12]

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  • I just want to mention, in the last few minutes, that there are other drugs that are being tested in humans, including the statins, triptolide, a Chinese herb,* EGFR inhibitors, and tyrosine kinase inhibitors.

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  • There are other drugs that have shown promise in animals, like caspase apoptosis inhibitors; the CDK inhibitors;* the tumor necrosis factor (TNF)-α inhibitor, etanercept, which is FDA approved for use in arthritis; metformin; peroxisome proliferator-activated receptor (PPAR)-γ agonists; and curcumin,* which has shown potential in animals and I am sure will be studied in humans in the future.

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Closing Remarks

  • Dr Cowley: I want to thank both of you and ask for your final thoughts. I think the one point that Charles mentioned that I would like to reiterate is the idea that we are probably not going to solve the treatment of this disease with one drug. There is not going to be a magic bullet. When we are actually successful in altering the progression of this disease, we are probably going to have to target a number of different abnormal mechanisms, probably with combination therapy.

    Dr Edelstein: I think patients will be on combination therapy because most patients will already be on an ACE inhibitor. If a novel therapy is added, we will have that therapy in addition to an ACE inhibitor or an ARB.

    Dr Chapman: I think we are learning so much now about how kidneys grow in PKD and how early cyst growth occurs. Timing is going to be important, and I think early on in the course of the disease is when we need to prevent or delay progression to dialysis or the need for a transplant. I think once we understand the effects of the drugs and their safety profiles better, we will be able to identify who the high-risk patients are as early as possible and really target those individuals.

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  • Dr Cowley: Please take a few moments for a brief post-assessment survey by clicking on the Earn CME Credit. The CME posttest will follow. Please also take a moment to complete the program evaluation at the end. I want to thank both Dr Chapman and Dr Edelstein for participating, and I want to thank those of you who watched this program. Thank you.

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*This section includes discussion of non-US FDA-approved therapies.

†The US FDA has not approved this medication for this use.

This transcript has been edited for style and clarity.

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