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Renal Resource Centre 37 Darling Point Poad, Darling Point, NSW 2027 AUSTRALIA Telephone: 61 2 9362 3995 9362 3121 Facsimile: 61 2 9362 4354 Freecall: 1800 257 189 Click here for our location map |
Welcome
Managing Your Kidney Disease
Anaemia Management and EPO
Developments in Therapeutic Interventions in PKD
Effects of Chronic Caffeine Consumption
Factors Affecting Disease Progression
Cholesterol Lowering Drugs May Help PKD Patients
Race to Clone Organ Transplant Pigs
High Blood Pressure & Maintaing a Low Salt Intake
Life Insurance & Genetic Testing
Health Insurance Consultants
Health Tips for Living with PKD
2nd July 2003
Dear Readers,
It's all good news dear readers. It's been a long time since the last newsletter but in that time there have been some very encouraging developments in the understanding of PKD, including the mechanisms involved in the development of cysts, possible strategies in slowing cyst progression and the human trialling of medications designed to slow the progression of PKD.
I believe that the future for those with normal kidney function and for the next generation of those with PKD, the future is very encouraging. For those of you whose kidney function is significantly reduced and declining and the inevitability of dialysis and transplantation is a reality, let me assure you that treatment today is extremely efficient and can provide an excellent quality of life. There is no reason why all your usual activities cannot be accommodated.
It is important for your future well being that you regularly attend your renal physician so that blood pressure can be monitored and weel controlled. Good blood pressure control is the single most important strategy to slow the progression of PKD.
Some of you may also be following a reduced protein diet. Patients need close and continuous monitoring when they embark on a low protein diet. It is extremely valuable to discuss any dietary changes recommned by your renal physician (such as protein, phosphorous, salt or potassium) with your renal unit dietitian, who can review your current diet and advise upon the best way to implement the necessary changes.
Remember too, to discuss with your physician any other medications or alternative therapies you may be taking. It is very tempting to explore anything that may be touted as boosting kidney function. Be careful and be open and honest with your physician, who really is your best guide to protecting and prolonging the function of your kidneys.
I hope you find the information contained in the following pages useful. Please raise any questions that may arise after your reading with your renal physician.
You are also welcome to call me at the Renal Resource Centre if you or members of your family would like further information about living with PKD and the management of renal failure.
Best wishes,
Denise O'Shaughnessy
Senior Social Worker
Manager
Renal Resource Centre
Most people diagnosed with PKD want to know what they can do to remain healthy and prolong the function of their kidneys. There are several strategies which we know will help to achieve these goals.
Earlier diagnosis of PKD is occurring more frequently these days and so these measures are employed earlier and lead to better outcomes.
One of the mainstays of treatment is to ensure that blood pressure is kept within normal limits. This will prevent further damage to the kidneys caused by high blood pressure.
Secondly, in those patients who suffer from anemia as a result of the kidneys' decreased production of erythropoietin, medication which is a genetically engineered version of that hormone can be prescribed to restore haemoglobin levels to an acceptable level. Not only does this restore energy levels but treatment of anemia prevents long term heart disease. The introduction of a synthesised form of erythropoietin (EPO) in the early 19990s was a major breakthrough for those with kidney disease. This medication can be prescribed before the onset of the need for dialysis treatment and can significantly improve an individual's quality of life.
Dietary modification has for years been prescribed to those with renal impairment in an effort to prolong kidney function.
It is important before embarking on any changes to discuss them with your renal physician. The following are guidelines only.
Protein restricted diets are based on a prescription of a reduced protein intake, based upon the level of kidney function and the patient's weight. Animal studies have in fact shown that a low protein diet can help to slow the progression of PKD. One must however guard against malnutrition, which has been found to be associated with poorer long term outcomes.
Supervision of dietary changes by a renal dietitian can help to ensure an adequate nutritional intake.
Two recent studies have failed to demonstrate any beneficial effect of a lower protein intake on the progression of PKD. However, the results should be viewed with caution. These studies were poorly designed, being too short in duration and manipulating other variables, such as blood pressure, which may affect the progression of renal disease. Many physicians will prescribe a reduced protein diet to slow progression and to relieve symptoms caused by excess urea, a waste product of protein metabolism.
Diets based on plant proteins help lower blood pressure and may help to slow the growth of cysts in PKD. Sources of protein are meat, fish, chicken, milk, cheese, eggs and legumes. A general recommendation is to have no more than 0.8 gms of protein per Kg of body weight per day.
Studies in laboratory animals show that soy protein slows progression of PKD. Epidemiological studies from Asia show that people who regularly eat soy protein may have slower rates of PKD than those in western cultures who do not consume soy. Soy contains anti-oxidants (isoflavines) and essential fatty acids that help reduce inflammation in the kidneys.
Low sodium diets (<3,000 milligrams per day) help reduce blood pressure and in lab animals helps slow the progression of PKD. Caffeine may hasten the progression of PKD by elevating blood pressure.
Studies with rats and some human studies show that ingestion of omega-3 fatty acids, a type of essential fat, may help some types of kidney disease by reducing inflammation in the kidneys. Many of us are deficient in these fats from eating processed foods. Good dietary sources are walnuts, cold water fish (salmon, cod, flounder, sole), soy beans and leafy green vegetables.
Recent studies have found that people with PKD and other kidney diseases may be mildly insulin resistant. High insulin levels are linked with heart disease and possibly faster rates of PKD progression. Fibre helps slow down the digestion of carbohydrate foods and may help reduce some of these risk factors. Good sources of fibre are whole grains, legumes, nuts, vegetables and fruit. Aim for at least 30g of fibre per day. If you have been told to follow a low potassium diet, your intake of these high fibre foods may be limited. Speak with your dietitian about this.
While many animal studies suggest that these dietary changes may modify the progression of PKD, more research is needed before any of these recommendations can be proven to work in humans.
However, until that time, you can be confident that all these dietary and lifestyle suggestions are safe and can improve anyone's health. Remember that slow change is more likely to be lasting change. Start slowly with your dietary changes and in time, your tastes will adapt.
New approaches to the treatment of kidney disease will benefit many people diagnosed with PKD. Early diagnosis and management of chronic kidney disease are improving outcomes. The focus of management is now on treating disease symptoms and the effect of kidney disease on other organs, slowing the rate of progression of disease and delaying the need for dialysis and transplantation. Doing this well rests upon the participation of both patient and physician as active partners working towards the same goal.
The most important tasks early in treatment are to reduce elevated blood pressure (to prevent further damage to the kidneys and other organs) and to treat anaemia. Most people with kidney failure suffer from anaemia. This is due to the kidneys reduced ability (less so in people with PKD) to produce the hormone, erythropoietin (EPO). EPO stimulated the bone marrow to produce red blood cells, which transport oxygen around the body. Reduced EPO production results in lowered levels of haemoglobin and anaemia. Anaemia may lead to an increased risk of heart disease, which is a major risk factor for dialysis patients and of course, to significant fatigue. However, this fatigue can often be overlooked and undertreated as it often develops slowly and people often accommodate to it. It is only after treatment has commenced that they realise just how tired and worn out they really were. It is important to recognise these symptoms and report them to your physician.
Your renal physician will monitor your haemoglobin levels and prescribe an injectable medication (either Eprex or Aranesp), which is a genetically engineered version of EPO.
Treating anaemia early in the course of chronic kidney disease and prior to the commencement of dialysis, can offer benefits such as enhanced functional status and increases energy levels and work capacity. Early treatment can also reduce the risk of damage to the heart.
Your physician will also be monitoring levels of phosphate and calcium, which are dependent upon the healthy functioning of kidneys. If these minerals are out of balance, bone disease can result. Bones can become more brittle and prone to fracture. However, your physician can prescribe medications to correct this imbalance, thus minimising the risk of long term damage to your bones.
It is important that you regularly consult not just your GP but also your renal physician, who is expert in monitoring and treating chronic kidney failure and its associated effects. Good management may prolong your kidney function and will certainly ensure a better long-term outcome for you, even if you do eventually require dialysis or transplantation.
Several very encouraging developments in arresting or retarding the growth of cysts in kidneys have been reported in the last 12 - 18 months in the literature. These reports are from laboratories specialising in research into PKD.
Some exciting news about drug therapy to retard cyst growth has been released. I believe this is very promising for future treatment of PKD.
Drug company AVI BioPharma has created a new drug that slows cyst progression in lab animals with PKD. NEUGENE has been in the development phase for several years. Successful tests on lab animals means the drug will move to Phase 1 clinical trials in humans soon, under the guidance of William Bennett MD, Director of Transplantation Medicine at Legacy Good Samaritan Hospital, Portland Oregan. These trials will investigate the efficacy and safety of the new drug in patients with PKD. (Kidney International)
The Rainbow Centre for Childhood PKD have demonstrated that cystic kidneys in animal models and human ADPKD (autosomal dominant PKD or Adult PKD) and ARPKD (autosomal recessive PKD or infantile PKD) have altered expression of specific proteins, called growth factor receptors. These receptors, particularly the epidermal growth factor (EGFR) mediate the cellular proliferation necessary for the growth of cysts in PKD. It has therefore been proposed that increased EGFR expression in cystic kidneys might provide a direct target for new therapies to reduce cyst growth and expansion in PKD.
In the February 2000 issue of Kidney International, the above group published a study in collaboration with Wyeth Ayerst research, in which an EGFR-specific tyrosine kinase inhibitor (EKI-785) was utilised to reduce the activitiy of EGFR in an animal model of ARPKD. It was demonstrated that EKI- 785 is a potent, nontoxic compound that dramatically reduced cystic lesions and improved kidney function in this model. The results suggest that targeting the cystic EGFR with EKI-785 and similar compounds may have value in the treatment of human ADPKD and ARPPKD.
Again in collaboration with Wyeth, the Rainbow Centre has extensively tested a second generation EGFR inhibitor. The new compound referred to as EKB, was found to be more effective than EKI-785 in preventing cyst development and growth and demonstrated greater activity following oral administration. Preliminary results suggest that better results can be obtained if treatment is initiated early in the disease process. However, there is a point, late in the disease, where EKB is ineffective in arresting cyst growth or improving kidney function. The implications of this are clearly very important in extrapolating this work to future human trials.
Currently EKI and EKB are being utilised in a series of additional animal studies to treat models of ADPKD in collaboration with Dr. Torres' laboratory at the Mayo Clinic and Dr. Somlo's lab at Yale. Extensive toxicological studies are also in progress.
New therapeutic targets are the ligands or "keys" that fit into the receptor "lock" and result in activation of the receptor. Developing pharmacological agents that limit the availability of ligands capable of activating the EGFR is a different, complementary approach that is also being taken at the Rainbow Centre. It was reported in October 2000 that these new agents are effective in reducing cyst formation and improving kidney function in an animal model of ARPKD. These agents can be administered alone or in combination with EKB.
Current studies are evaluating the effectiveness of developing combination therapy in the hopes of developing a maximally effective, minimally toxic treatment regimen to prevent cyst growth.
Wyeth has initiated Phase 1 Human trials using EKB, which are designed to determine if the drug can be tolerated without significant toxicity. TO date a small number of volunteers with advanced malignancies have been treated at low doses without serious toxicity. It is hoped that if effective doses can be administered safely in this Phase 1 trial, pilot studies in patients with PKD may commence in the next 6 - 12 months.
Sequencing of human genes in the Human Genome Project and sequencing the genomes of model organisms, such as worms, has led to the discovery that proteins in the PKD 1 and PKD 2 genes behave very similarly to a gene protein in a roundworm. The significance of this is that identifying tools to solve the mysteries of genetic disease can accelerate further biomedical research on the behaviour of these proteins. Using the model organism of the roundworm in PKD gene protein research is tremendously valuable.
Other gene research is focusing on the possibility that the PKD2 protein may function as a calcium ion channel. If it can be demonstrated that the PKD2 protein forms a selective ion channel that controls the influx of ions - perhaps calcium ions - into the cell as part of a cell - signaling mechanism, then it is possible that therapeutic drugs could be developed.
At present, 50% of the world's drugs are now channel blockers or activators of one sort or another. Numerous calcium channel interacting drugs have already been developed and could be used if it can be shown that the PKD2 protein is indeed a calcium ion channel. Calcium is known to be important to many cell-signaling processes. If PKD2 is disabled or inhibited in its cell-signaling, then it might be that the cell gets confused and starts making cysts. A calcium channel activator might be able to restore this activity and retard or prevent cyst formation.
This model suggests that the PKD1 protein picks up a signal from outside the cell and then physically interacts with the PKD2 protein in the cell membrane to cause the PKD2 protein to open its pore, allowing ions to flow into the cell. The ion flow is a signal to the cell to perform a particular function. In humans, the function remains a mystery; however, the normal function is disrupted by a mutation of PKD1 or PKD2, the result is cyst formation and the unknown function is mediated by nephron cells in the kidney. Important questions must be asked of this hypothesised mechanism. What are the signals that activate this mechanism; what are the downstream effectors in the cell; and what additional factors are responsible for adapting this signal transduction mechanism to the unique requirements of each tissue (e.g. kidney)? Somlo and Emmons who presented this hypothesis in Nature have definitely paved the way for some exciting research.
Beta-catenin is known to be involved in cell-signaling processes in colon cancer and has been intensively studies by cancer researchers. Dr. Janet van Adelsberg has been working to identify proteins that interact with the PKD1 proteins . Beta-catenin is a key player in the regulation of cell polarity, cell proliferation and cell morphogenesis, all related to what happens in the cyst development that occurs in ADPKD. Beta-catenins known to regulate cell division and cell proliferation. When Dr. Christine Perret introduced activated beta-catenin into mice, she demonstrated the development of polycystic kidneys in those mice. The study was designed to investigate colon cancer induced by expressing the beta-catenin gene in the intestine of the mice, but the gene was also expressed in the kidneys, with the mice not only getting colon cancer but also developing polycystic kidneys.
It is possible that PKD might be associated with a disturbance in the beta-catenin signaling pathway. Problems with PKD1 and PKD2 proteins may stimulate the production of beta-catenin, which turns on the c-myc gene, which can stimulate cell growth and proliferation! This theory, if true, is very exciting in that it opens the way for many therapeutic possibilities.
In a study of rats with ADPKD (autosomal dominant PKD), caffeine intake was shown to exacerbate hypertension. A study conducted by Drs. George and Judith Tanner at the Indiana University School of Medicine (American Journal of Kidney Diseases, Nov. 2001) demonstrated that rats with ADPKD who were given a solution of caffeine rather than tap water for drinking, from 1 month to six months of age, were found to have significantly higher mean arterial blood pressure than the controls, even without caffeine consumption. Chronic caffeine consumption had no effect on the blood pressure of the rats without ADPKD. With "low' doses of caffeine (=a person drinking 4 cups coffee/day), blood pressure was 15mmHg higher than rats with ADPKD who drank tap worker. In the case of "high" caffeine consumption (= 9 cups coffee/day), blood pressure was 22mm Hg than in the rats with ADPKD who drank tap water.
Examination of the kidney tissue revealed that neither the number nor the size of kidney cysts were affected by caffeine. These results do not support the speculation that caffeine increases cyst enlargement in polycystic kidneys by stimulating fluid secretion.
So what is the implication of this study? Well, high blood pressure is very common in people with ADPKD and studies in ADPKD patients indicate that control of hypertension is very helpful in slowing the progression of renal disease. Controlled studies will need to be conducted to establish whether similar effects of caffeine consumption on blood pressure are seen in people, as in rats.
Until such time, the authors suggest that it might be prudent for people with ADPKD to limit their intake of caffeine or at least, to monitor the effects of caffeine on their blood pressure.
Adapted from: ADPKD: Modification of Disease Progression
Dr Dorien Peters PhD, Prof MH Breuning PhD
Lancet 2001; 358: 1439-44
Many of you are of course desperate to know how, or in fact, if one can, slow the progression of PKD. Research is progressing in this area too and is very encouraging and answers the question that many of you have observed. If we all have the same gene, why do members of my family progress at different rates?
Progression of ADPKD, resulting in renal failure, varies between members of affected families, as well as between different members of the same family. In some people, kidney cysts are present in early childhood and progress to end-stage renal failure by age 40 years and yet others maintain unimpaired renal function throughout life. Several general factors affect disease progression
People with a mutation in the PKD2 gene have a milder progression of the disease than those with a mutation in the PKD1 gene. The median age of the onset of end stage renal failure in those with PKD1 is 53 years and in those with PKD2 is 69 years. Both groups have extrarenal complications but those with PKD2 are less likely to have hypertension, urinary tract infections and haematuria (blood in the urine).
Various mutations are seen in PKD genes. With few exceptions, every family has its own mutation. It has not yet been possible to correlate the various genetic mutations to clinical outcomes in PKD. However, for one specific group of patients (those with tuberous sclerosis and a severe form of infantile PKD), it has been found that all are missing most of the PKD1 gene and the neighbouring TSC2 gene.
Genes not directly associated with PKD might affect the progress of the disease. For example, the prognosis for patients with PKD is less favourable if one parent has primary hypertension. Also, risk of recurrence of kidney disease is increased in those who first have first symptoms of the disorder at a young age. Scientists are investigating the possibility that certain genes might modify the progression of PKD in human beings.
The journal, Nephrology Dialysis and Transplantation, has reported that in animal studies, maintaining normal cholesterol levels in the blood can improve kidney function. Investigators at Leiden University Medical Centre in Tilburg in the Netherlands, examined the usefulness of simvastatin, an inhibitor of cholesterol formation. Simvastatin not only reduced blood cholesterol by 25 %; it significantly elevated filtration rates and blood flow through the kidney. Further trials are needed but these types of drugs may prove useful to prevent the decline in kidney function in ADPKD patients.
Many of you are probably wondering what is happening as far as research into the cloning of organs to solve the shortage of kidneys for those with renal failure and wishing to be transplanted.
After a breakthrough by the firm that created Dolly, the first cloned sheep, two groups are locked in a race to be the first to develop technology that will allow pigs' organs to be transplanted into humans without rejection.
Pigs' kidneys, hearts and other organs could help solve a shortage of donated organs. These 'knockout" piglets (named because they do not have one of the genes that causes the human immune system to reject transplanted organs) bring the prospect of transplants from animals a step nearer.
PPL Therapeutics, which created the pigs and hopes to start clinical trials within four years, said analyst estimates suggest that the market for solid organs could be worth $US5 billion a year while cell therapies based on pig tissue may add another $6 billion. PPL says successful cloning of knockout pigs has removed a key obstacle in the development of xenotransplantation.
While issues like the possibility of introducing pathological viruses into humans are a concern (particularly in light of the SARS epidemic), the idea of using animal organs for human transplantation is likely to trigger a fierce ethical debate.
Sodium is the main ingredient in salt, a very common ingredient in modern everyday diets. Sodium causes the body to retain excess fluid, in part causing the blood pressure to rise, which, of course, is not desirable, especially if you already have an underlying kidney disease. Many people think they eat a low salt diet but even if they never pick up a salt shaker, they probably eat more salt than they realise.
Many processed and fast foods contain large amounts of salt to help preserve them and to make them taste better and to create a thirst for soft drinks sold in fast food outlets.
It is commonly advised that you should lower your salt intake if you have high blood pressure. A common recommendation is to have no more than 2,000mg (1tsp table salt) each day. Check with your physician or dietitian about the amount that is appropriate for you.
The Following Advice May be Useful In Maintaining a Low-Salt Intake
Taken from "Health Tips for Living with PKD" PKD Foundation
This booklet contains nutrition, lifestyle and resource information. It can be ordered for $US15 from the
PKD Foundation
4901 Main Street Kansas City
MO 64112-2634
USA
or borrowed from the Renal Resource Centre Library.
Tel: 02 9362 3995 or Freecall: 1800 257 189
The Investment & Financial Services Association Ltd has produced a fact sheet, "The Facts on Life Insurance and Genetic Testing in Australia". IFSA is the national not-for-profit organisation representing the life insurance industry to Government, regulatory agencies, consumers and the community.
Under the IFSA Genetic testing Policy, IFSA members:
Trying to work out which private health insurer provides a value for money service can be like trying to work your way through a maze.
If you require assistance in determining which private health insurance provider can best meet your needs, you may wish to contact Health Insurance Consultants who provide a free advisory service to members of the public.
Health Insurance Consultants
PO Box 1000
Eltham 3095
Email: hica@ozemail.com.au
Tel: 03 439 9888 or
Fax: 03 9431 4469
This booklet, edited by Dr Arlene Chapman, has recently been released by the PKD Foundation, 4901 Main Street, Suite 200, Kansas City MO 64112 and can be ordered for $US 10.00 and $US5.00 postage.
It is a useful booklet which addresses diet and PKD, women and PKD, exercise and pain and PKD. It aslo contain some useful web sites regarding PKD, dialysis and transplantation.You may wish to borrow a copy from me at the Renal Resource Centre 02 9362 3995 or 1 800 257 189.
The annual conference organised by the PKD Foundation was held June 27 - 29 at the Mineapolis Marritt City Center, Minesota.
Information will be available on their website www.pkdcure.org
I think the following cartoon really sums up the idea that we can't always find the answers we want hear (no matter how hard we try) but trying to take control by searching for information is to be encouraged! Believing and following the advice of the experts is the next step.
DISCLAIMER: The PKD Association does not recommend or endorse any drugs, treatments or procedures reported in this Newsletter. The information is intended to keep you informed and we strongly recommend that you discuss any drugs, treatments or procedures mentioned with your doctor.
Renal Resource Centre