Polycystic kidney disease (PKD), a genetic disorder that causes the formation of renal cysts, is a leading cause of end-stage renal disease (ESRD). No drug treatment options are currently available. However, as researchers gain new understanding of the mechanisms that cause PKD, promising therapies are emerging.
“Our rationale with these new treatments is not to cure PKD but to slow it down,” said Vicente E. Torres, MD, PhD, Professor of Medicine and Chair of the Division of Nephrology and Hypertension at the Mayo Clinic. “If you can slow the progression of the disease enough to make it irrelevant as far as causing kidney failure, that would be a very good outcome.”
Mechanisms of PKD
As the cysts of PKD increase in number and become enlarged, they destroy kidney function, and renal failure develops. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, while autosomal recessive polycystic kidney disease (ARPKD) is rare and is one of the leading causes of childhood end-stage renal disease.
In addition to the kidneys, PKD can affect other organs, including, most commonly, the liver, where cysts can also develop. Other manifestations of the disease can include blood vessels, Dr. Torres said.
Cyst formation occurs when ADPKD genes—PKD1 and PKD2—mutate and inhibit the formation of tubules.
“For these tubules to develop and maintain their normal structure, the cells have to have a blueprint of how to divide and keep that single structure,” Dr. Torres said. “PKD1 and PKD2, the genes that cause ADPKD, are very important. When these genes are mutated, the cells divide in all directions and instead of forming a long cylinder, they form a sphere. That's how cysts develop.”
Polycystin-1 (PC1), polycystin-2 (PC2), and fibrocystin/polyductin (FC/PD) are proteins encoded by ADPKD genes, and they are critical to the development of cysts. In particular, these proteins give information by controlling signaling mechanisms inside the cell, including the regulation of intracellular calcium homeostasis and levels of cyclic adenosine monophosphate (cAMP), Dr. Torres said.
In ADPKD, levels of calcium appear to be lower than normal, while concentrations of cAMP appear to be higher. “cAMP stimulates the proliferation of cells and fluid secretion, and these are both important components for cyst formation,” Dr. Torres said.
A prevailing view is that these proteins form a complex sensor for detecting fluid flow, said Peter C. Harris, PhD, Professor of Medicine and of Biochemistry and Molecular Biology at the Mayo Clinic. If this process doesn't work properly, cells proliferate more than usual and cysts grow, he said.
A growing understanding of these molecular and genetic mechanisms has allowed the development of new therapies, including those that aim to reduce levels of cAMP. The idea behind these treatments is that by blocking certain receptors cAMP can be lowered and cystic growth can subsequently be slowed, Dr. Harris said.
Because cAMP plays such a pivotal role in the pathogenesis of PKD, “the ability to hormonally modulate cAMP in a cell-specific manner” provides opportunities for targeting therapies, Dr. Torres wrote in an article in Seminars in Nephrology (2008;28:306–317). The arginine vasopressin (AVP) V2 receptor is an attractive target for this reason, Dr. Torres said.
Vasopressin V2 receptor (VPV2R) antagonists have shown success in lowering renal cAMP and slowing cystic growth by blocking V2 receptors, Dr. Torres said. Vasopressin acts on V2 receptors and regulates adenylyl cyclase. V2 receptors in the collecting duct and distal nephron, however, are overexpressed in polycystic kidneys.
“Patients with ADPKD are not usually able to concentrate urine, and they pass more urine than most people,” Dr. Torres said. “They tend to have levels of vasopressin in the blood that are increased and that increase cyst growth. V2 receptor antagonists block cAMP, and the hope is that will slow down the growth of cysts.”
The data, thus far, is indicative of a major advance in potential ADPKD treatment, but Dr. Torres is quick to point out that everything is still based on animal studies. Clinical trials—including one in Phase 2 and one in Phase 3—are going on right now. Past animal studies have demonstrated the importance of AVP in cyst formation, and Dr. Torres expressed optimism that clinical trials would show the benefit of VPV2R antagonists.
“In several animal models, this approach has worked very well,” Dr. Harris agreed. “It slowed dramatically or even halted cystic disease with this treatment, and it will be interesting to see the results of current clinical trials.”
Another experimental family of drugs currently being tested in clinical trials is somatostatin analogues. Somatostatin is an amino acid peptide that inhibits production of cAMP in the tubules and bile ducts.
Somatostatin analogues, aimed at SST2 receptors, have so far been shown to slow cAMP accumulation in the kidneys, and octreotide, a long-acting synthetic somatostatin analogue, was shown to be effective in reducing renal volume expansion, a marker of cysts.
“Studies have shown that these somatostatin analogues are helpful to the liver as well as the kidneys,” Dr. Torres said. “There are a number of clinical trials, including one here in the US, one in Italy, and another in the Netherlands.”
Although vasopressin V2 receptor antagonists and somatostatin analogues act in different ways, the end result is the same: reduced levels of cAMP, Dr. Torres noted.
An additional family of potential drugs is mTOR inhibitors, which have been used in the past as part of immunosuppressive therapy after organ transplantation. In studies of three animal models of PKD, researchers showed that rapamycin significantly slowed the rate of cyst expansion by targeting the mammalian target of rapamycin (mTOR).
Two mTOR drugs are currently in clinical trials run at the Cleveland Clinic, in Italy, and in Zurich. Everolimus, another mTOR inhibitor shown to be successful in slowing cystogenesis in animal studies, is also being studied in a clinical trial, Dr. Torres said.
Role of Cilia
As recent research has uncovered more of the mechanisms related to the pathogenesis of PKD, the critical role of cilia has become more and more apparent.
In fact, until relatively recently, the cilium “has suffered from a severe lack of respect,” said Bradley Yoder, PhD, Professor in the Department of Cell Biology at the University of Alabama at Birmingham.
It was a pretty big surprise when it became clear that cilia play a significant role in renal physiology, he added.
Polycystin-1 and polycystin-2 are localized to the primary cilium or at the basal body at the base of the cilium.
Scientists stumbled on the fact that these PKD-related proteins are localized to cilia when a group of scientists led by Maureen M. Barr, PhD, were examining mating behavior of the nematode Caenorhabditis elegans.
Dr. Barr found that the genes that were necessary for the worms to mate—PKD1 and PKD2—were in the cilia. These model organisms do not have kidneys, but further examination revealed that those genes were localized in the cilia in mammals as well, Dr. Yoder said.
“We don't know what role exactly the cilia play yet, but we do know that there has to be cell proliferation and fluid secretion for cysts to develop rapidly. We have to figure out more about how they work before we can begin to fix problems.”
Still, because a consensus has been reached that genetic defects related to renal cyst development localize to cilia, new research—particularly on primary cilia on tubule epithelia—could mean new treatments for PKD, Dr. Yoder said.
Animal models have demonstrated that without properly functioning primary cilia, cysts develop, Dr. Harris said. The microtubule-based organelle acts as a mechanosensor and is associated with calcium flow into the cell.
Cilia appear to be involved in many different signaling pathways, which could prove helpful for future treatments, Dr. Yoder said.
“The implications are that if we could understand the signal that tells cells to form part of a cystic structure, we could go in and block that signal, making the cell behave as it should,” he added.
“We might be able to stop cyst formation, and we also might be able to intervene in lots of other ciliopathies like blindness, obesity, and skeletal defects. There is new appreciation for all of the roles that this once-forgotten organelle plays.”
Advice for Physicians
It is still unclear if and when many of these treatments will become available, and the best course of action for nephrologists treating patients with ADPKD is to pay careful attention to control of risk factors like hypertension, hyperlipidemia, and high cholesterol, Dr. Torres advised.
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In addition, pain management and prevention of urinary tract infections (UTIs) are also important because untreated UTIs can potentially lead to cyst infections, which are difficult to treat.
“Right now, the best thing to do is keep blood pressure under control and to urge patients to lead a healthy lifestyle,” Dr. Torres said. “I also think physicians should stay informed about new research because sometime in the not very distant future I hope these drugs will be available for use.”
© 2009 Lippincott Williams & Wilkins, Inc.