The following are current studies of the PKD Research Group at the University of Colorado Health Sciences Center.

PKD Study of Children; PKD Genetic Study; PKD Apoptosis Study; PKD Liver Study;

HALT PKD Study

PKD Study of Children

We are conducting this study of children with PKD to determine if treatment with a particular type of blood pressure medication currently on the market, called an angiotensin converting enzyme inhibitor (ACE-I), will slow renal cyst growth in children and young adults with PKD.  Eighty-nine children and young adults (age 5 to 21 at the start of the study) have enrolled in this clinical study.  We monitor the children’s blood pressures monthly and each child visits the Pediatric Clinical Research Center at the Children’s Hospital annually.  The annual visits include an abdominal ultrasound, an abdominal MRI (magnetic resonance imaging), a cardiac echocardiogram, and urine and blood collections. The study includes children both with and without high blood pressure.  The children with high blood pressure all receive treatment, but half are given medication to reduce their blood pressure to the usual goal (below the 90^th percentile) and half are given medication to further reduce their blood pressure to the 50^th percentile.  Half of the children without high blood pressure receive treatment with an ACE-I, and the other half do not receive treatment unless they develop high blood pressure.  The treated children receive enalapril (a type of ACE-I), and if the blood pressure remains high they are treated with other anti-hypertensive medications as well.  We hope to show that the kidneys of the children receiving treatment (or more treatment) grow at a slower rate than the other children’s kidneys.  We believe that large, fast-growing kidneys will eventually lead to kidney failure (decades in the future for most children), but perhaps by slowing the kidney growth at a young age we can delay or prevent renal failure in the future.  This study will be completed in early 2007.

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PKD Genetic Study

The goal of the Genetic Study is to identify genetic causes for the differences in severity seen in people with PKD. Some people with PKD have hypertension early in life and require renal replacement therapy at an early age. Other people with PKD, sometimes even family members of the more severely affected, have normal blood pressure throughout their lives and do not reach end-stage renal disease until their 70’s or 80’s, if at all. These differences could be due to environment, diet, the type of ADPKD (PKD1 or PKD2), the specific mutation in the PKD gene, or non-PKD genes which influence the expression of PKD (modifier genes). It is known that, in general, families with their PKD gene on chromosome 4 (PKD2) have milder disease than families with their PKD gene on chromosome 16 (PKD1). There are a few studies that show that some variation between families is likely due to the particular mutation in each family. But the differences observed within families are due to modifier genes, environment or diet. Since environment and diet are exceedingly difficult to characterize, we are continuing with our study of modifier genes. In order to accomplish this, we first need to determine which of our PKD families are PKD1 (chromosome 16) and which are PKD2 (chromosome 4). We are doing this by gene linkage analysis, which often requires DNA on several affected family members, and by mutation screening, which theoretically requires DNA on only a single affected family member, but can be assisted by DNA from other family members. (When a mutation in a gene is found, it could be the mutation actually causing the disease or it could be a normal variant with little or no effect on the disease. Finding the mutation in other affected members and not in unaffected family members could help clarify this.) We are obtaining DNA on family members by requesting a blood sample or a mouthwash sample (we supply mouthwash which is swished in the person’s mouth and then returned to us).

The first potential modifying gene we are studying is actually a PKD gene, although not the one causing the disease in the subject. We are looking at the “good” PKD1 gene, the one from the unaffected parent, to see if variations in this gene can affect the disease severity. This gene is called the wild-type allele. The current theory of cyst formation in PKD is that the wild-type allele in a particular kidney cell undergoes a mutation, and, in combination with the “bad” PKD gene inherited from the affected parent, causes a cyst to form. This is called the “two-hit” model. It could be that certain wild-type alleles are more likely than others to undergo a mutation. We are looking at this possibility in a number of large families with PKD1. (If we had enough large families with PKD2 we could see if a similar process occurs in PKD2.) Other potential modifying genes related to PKD1 are the gene for PKD2 on chromosome 4 and the gene for ARPKD on chromosome 6. It is possible that the proteins produced by these genes influence the expression of PKD1; in fact, there is evidence that the protein produced by the PKD1 gene interacts with the protein produced by the PKD2 gene.

The next step in looking for potential modifying genes will be a genome screen, focusing initially on a subset of the most highly discordant families (families with both mild and severe disease), followed by replication in families with severe ADPKD. Additional markers in regions where significant linkage is found in both samples will then be typed in all families in order to pinpoint the specific modifier gene(s). A final analysis will be performed to estimate the relative influence of different sources of phenotypic variability, and to investigate the genetic and environmental correlations among different phenotypes.

A questionnaire regarding the time of onset of the first symptoms of ADPKD and trends in the diagnosis of ADPKD was sent to over 1500 people on our mailing list. Over 600 people have responded, for a response rate of greater than 40%. The surveys have been scanned into a database and we are ready to proceed with analysis.

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PKD Apoptosis Study

Apoptosis is the programmed cell death of cells within the body. This programmed cell death relies on a special group of proteins, called caspases, in order to take place. In people with ADPKD, apoptosis is thought to play a role in the loss of normal cells in the kidney and this loss of normal cells will cause the kidney itself to become damaged and ultimately nonfunctional. The long-term goal of this study is to learn how apoptosis and caspases play a role in the course of ADPKD and hopefully to change the course of the disease through the application of medications that inhibit caspases.

This year we have examined the pathways of apoptosis involved in the PKD in the Han:SPRD rat. There are two major pathways leading to apoptosis, the “death receptor” pathway and the “stress” pathway. A number of laboratory tests were used to examine the kidneys from rats with one type of PKD. These tests pointed to the “stress” pathway rather than the “death receptor” pathway. Understanding the processes involved in apoptosis in ADPKD may lead to treatments to prevent apoptosis and prolong kidney survival. We have developed a method of delivering caspase inhibitors to the rats, using an osmotic minipump that is inserted into the rats at age three weeks. We are also developing a colony of PKD2 knock-out mice for use in future studies.

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PKD Liver Study

Cysts in the liver are the most common manifestation of ADPKD outside of the kidney.  Most people with PKD over age 40 develop liver cysts.  Although the liver continues to function, the liver can become grossly enlarged which causes pressure and pain. Little is known about the cellular mechanisms involved in the formation of liver cysts.  We have been studying the regulation of growth and secretion in cholangiocytes, the epithelial cells affected by hepatic ADPKD.  We have examined human liver cyst tissue and the fluid from human liver cysts, and we found a striking increase in the presence of cytokine IL8, a compound related to inflammation.   Other studies are continuing on the human samples.  We have also developed a mouse colony of cpk mice, a model for PKD.  Studies of the liver cysts in the cpk mice indicate that epidermal growth factor (EGF) is necessary for liver cyst formation; however, we did not find elevated amounts of EGF in the human samples.  We are continuing to look at the role of growth factors in liver cyst formation in PKD.

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HALT PKD Study

The University of Colorado Health Sciences Center was chosen as one of four Participating Clinical Centers in a multi-center study of the effect of blocking the renin-angiotensin-aldosterone system on renal growth and function in people with ADPKD. We have met with the researchers from the other study sites (the Mayo Clinic, Emory University, and Tufts/New England Medical Center), the Data Coordinating Center for the new study (Washington University in Saint Louis), the National Institutes of Health (NIH), and a panel of external advisors chosen by the NIH. The protocol is now completed, the data entry forms are ready, a drug manufacturer has agreed to supply some of our medication needs, and we are working out the details of approval by the local patient safety review boards.  The study is scheduled to begin in late 2005.

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Revised: 10/14/05.