In the past half century, tremendous advancements have been made in medicine, but among the most profound has been the discovery of the molecular biology of DNA. This has opened new dimensions in both the diagnosis and the therapy of many diseases. It has also helped us expand our understanding of the mechanisms of clinical illnesses. Working with DNA has enabled scientists to confirm earlier observations dating as far back as the eighteen hundreds when Gregor Mendel made observations on genetics and inheritance using pea plants.

1. With understanding and discovery we face new social, economic and ethical problems related to the discovery of DNA: As we fine tune our diagnostic skills, we will be able to predict which children will develop disease, even before birth. Concerns exist that insurance companies will either charge a higher premium or not cover families with an inherited genetic disease. Such action could deny care to the very people who need it. Also, there are concerns that patients with a genetic disorder will be skipped over for promotion in their jobs. The PolycysticKidney Foundation is seeking support for a bill that will protect individuals with inherited disorders from discrimination either by employers or by insurance companies, H.R. 1227, the Genetic Information Non-Discrimination Act.

2. As gene therapy evolves, it may be possible to take a medication that is really a gene patch to replace a defective gene. However, will someday parents use this technology to “order up their children” from a menu – a super athlete, an intellectual, straight hair, blue eyes? This could be very troubling for the future. Though no one might mind if we were able to simply clone concert pianists and super athletes, it might be frightening if an evil despot were able to clone his own army. Though these events are very remote, and right now might exist only inthe pages of fiction, history has shown there are no surprises when it comes to technological advancement, either for the good or the bad of mankind.

3. As we develop research from stem cells that contain the DNA content of an entire human being, we create a conflict between religions that feel this goes against their belief and patients who feel that their relief of a treacherous disability should be the end point that supersedes religious dogma. This is a very sensitive, passion-loaded issue in which society must reckon.

4. To bring any therapeutic agent to market and have it available as a prescription item for consumers is extremely expensive, costing in the high millions of dollars. This holds true for a biological substitute such as a replacement enzyme as well as for a pharmaceutical agent. In illnesses such as hypertension or diabetes, thedevelopment costs can easily be distributed over the vast population that acquires these illnesses. However, many genetic diseases are extremely rare, and though the benefit of therapeutic biologicals is great, the fundamental economics of an already expensive healthcare system may constrain both their development and their use by those who can benefit. This is creating an ethical dilemma for society and the medical profession.

5. Meanwhile, while society irons out these issues, our purpose is to make the public aware of the role that genetics plays in kidney disease. We will discuss six topics, some you have undoubtedly heard of some of these, but others are quite rare:

                        1. Polycystic Kidney Disease

2. Alport’s Syndrome and thin membrane disease

3. Von Hippel Lindau Syndrome

4. Gitelman, Bartter and Liddle Syndromes

5. Congenital Malformations of the Genitourinary tract

6. The genetic basis for diabetes and hypertension

Polycystic Kidney Disease

Polycystic Kidney Disease is the most common genetic kidney disease that affects one in 400 live births. According to Dan Larson, president and CEO of the PKD Foundation (http://pkdcure.org) there are more than 600,000 Americans and 12.5 million people worldwide with PKD. This equates to more than Down’s syndrome, cystic fibrosis, muscular dystrophy, hemophilia, sickle cell anemia and Huntington’s Cholera combined. This disease is inherited as an autosomal dominant trait. Each parent contributes one chromosome each to a child. In PKD most people have a defect in chromosome 16. The chromosome is made up of genes that contain DNA, which is like computer code for the body. Each parent has a 50 percent chance of passing a gene. If one parent contributes the gene for brown eyes and the other the gene for blue eyes, the dominant brown eye gene wins and the child is born with brown eyes. In PKD, the parent who contributes the abnormal gene wins, and that is why it is so common. Over 60 percent of people who inherit PKD develop end stage kidney disease. It is also associated with brain aneurysms, stroke and hypertension. The defective gene causes kidney cells that regularly form tubules (tubes) that transport fluids through the kidney to instead form sacs of fluid called cysts. These perpetually fill with fluid and multiply. As they do they crowd out normally functioning kidney tissue. The kidney may grow from the size of a fist to the size of a football. Sadly, in the end, the kidneys no longer carry out bodily functions and dialysis or a kidney transplant is necessary.

Although there is no cure for PKD at this time, according to Larson, we have gone in the past twelve years from discovering the gene that causes PKD to seven clinical drug trials in humans. He cites these studies as examples of how through scientific collaboration between the private industry and the National Institute of Health can make a difference in the lives of kidney patients.

Alport’s Syndrome

Alport’s Syndrome is a disorder of collagen. You are already familiar with collagen, as it is a protein polymer. Protein polymers make up many objects of daily living – silk ties, shoe leather, Jell-O. Collagen is a protein that provides support for body tissues. It can absorb ten times its weight in water, and makes up one third of all human proteins. It is also the protein responsible for aging – as one ages, the cross links between fibers increase. There are four types of collagen in humans, and it is Type IV that is associated with Alport’s syndrome. In Alport’s collagen, protein chains self-braid to form a triple helix. These then join together and form the support structure for skin, partsof the ear and eye, and the kidneys. A mutation in any one of three genes that encode collagen chains will cause one of the helices not to form. Although other helices may substitute, the glomerular filter will be weaker and fails over time. The gene that is most likely to cause Alport’s syndrome is on the X chromosome, and the disease is more common in men. Women can develop Alport’s at an older age through lyonization, the same process that causes women to develop Fabry’s disease. Alport’s disease is characterized by proteinuria and in the adult variant, renal failure occurring past the age of 30, associated with hearing loss and a lens abnormality known as anterior lenticonus. Family members may have hematuria (blood in the urine). In an alternate type of Alport’s syndrome, the abnormal gene is on one of the autosomal chromosomes, not the sex chromosome. Thus fathers and mothers may have milder manifestations such as hematuria. Benign familial hematuria is a condition where one of the collagen genes is abnormal, but there is only a slight decrease in the collagen helix needed for healthy kidneys. Although this condition is autosomal dominant, like polycystic kidney disease, it causes only hematuria, and only rarely proteinuria, hypertension or kidney failure.

Right now there is no treatment for Alport’s Syndrome. However, a physician who suspects the disease should perform a very careful family history, and should also look closely for hearing and eye abnormalities. Since collagen fibrils can appear in skin, and others do not, a skin biopsy may be helpful in distinguishing the ab x-linked from the autosomal recessive types. It works about 85 percent of the time. It is only valuable when negative, as it would then strongly suggest an x-linked variety. A kidney biopsy will make the diagnosis.

Von Hippel Lindau Syndrome

This, like polycystic kidney disease, is autosomal dominant, and is characterized by renal cell carcinoma and blood vessel tumors on the skin, retina, spine and brain (cerebellar hemangioma). The disease may be associated with a tumor of the adrenal glands that causes hypertension, known as pheochromocytoma. The VHL gene encodes a molecule that promotes the breakdown of another molecule called the hypoxia inducible factor (HIF). HIF stimulates blood vessel formation. Renal cell carcinoma is a very vascular tumor, as are the lesions that appear on the retina and cerebellum.

Using genetics, the disease is easily detectable in relatives. Careful surveillance is necessary once the disease is diagnosed, as the mean age of diagnosis of renal cell carcinoma is 35 years old.

Gitelman, Bartter and Liddle Syndromes

Bartter Syndrome is characterized by salt wasting from the thick ascending limb of Henle. This is a part of the renal tubule that is responsible for resorbing salt. A defect would cause salt to be lost into the urine, leading to hypotension, hypokalemia (low serum potassium levels) and a metabolic alkalosis similar to what is seen with vomiting. The disease mimics the findings seen when the drug furosemide (Lasix) is administered. This is because furosemide also works at the thick ascending limb of Henle, the exact site as Bartter Syndrome. The genes responsible for this disorder have been identified, and it is autosomal recessive. The disease may present with growth abnormalities, and clinical trials with non steroidal anti-inflammatory agents such as indomethacin have been tried.

If Bartter Syndrome is similar to the use of furosemide, Gitelman Syndrome is similar to the use of hydrochlorothiazide. This defect is at the distal convoluted tubule, another part of the kidney tubule, and the area where the thiazide diuretics act. Patients with this condition have a milder course. It may first be suspected by finding hypokalemia. Therapy with magnesium and potassium supplements or potassium-sparing diuretics may be effective.

Liddle Syndrome is autosomal dominant, which means if you have the gene you have the disease. It is associated with hypertension present in childhood. Metabolic alkalosis and hypokalemia also accompany the hypertension, suggesting that there is an increased hormone known as aldosterone causing these findings. However, the defect is not an excessive hormone, but increased sensitivity to the hormone in the cells of the collecting duct, where amiloride, a potassium sparing diuretic acts. While the two disorders mentioned above cause hypotension because sodium retention was blocked, this disorder causes hypertension because the sodium transport is more active. Thus, therapy with amiloride is effective in controlling this disorder.

Congenital Malformations of the Urinary Tract

This relatively broad group of common disorders are said to affect approximately 10 percent of newborns and account for over 30 percent of all congenital malformations. They include the well known disorders of a solitary kidney or a dysplastic kidney (where one kidney fails to properly develop), an obstruction at the junctions of either the kidney or its ureter (a tube that carries urine to the bladder) or bladder reflux. These conditions, if untreated can lead to renal failure, and are a major problem in developing countries. They are also associated with a number of more rare diseases, such as those causing extra digits, skeletal abnormalities, cranialfacial (head and face) anomalies and ear malformations. If these disorders are present, it might be advisable for parents to consult a geneticist. As many of the genes and the nature of the hereditary of these disorders have been discovered and established.

The genetic basis for diabetes and hypertension

Much has been written about the Metabolic Syndrome, or Syndrome X – characterized by obesity, hypertension, hyperlipidemia and type 2 diabetes. This disorder is a risk factor for cardiovascular disease, and undoubtedly contributes to many of the cases of kidney disease and kidney failure that we see. The disease is characterized by a decreased sensitivity to insulin. Since insulin does not work as well as it should to reduce the blood glucose in a timely factor, many side effects of the excess sugar, the secondary hunger and obesity, the hypertension, lipid disorders and the effect of insulin itself can lead to the associated diseases that comprise this syndrome. The fact that this disease clusters in families has led researchers to believe that there is a genetic basis for this disease. Several leads have been traced, and there have been several promising genes thought to be the culprit, but to date there is no specific gene disorder that can directly explain all features of the syndrome.

References:

1. Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350:151-164.

2. Karetova D, Bultas J, Linhart A, Lubanda JC, Magage S, Uklikova P, Palecek T, Ledvinova J, Poupetova H, Dobrovolny R, Hrebicek M, Elleder M. Fabry disease - clinical manifestations and genetics. Acta Paediatr Suppl 2006;95:124-128.

3. Warnock DG, West ML. Diagnosis and management of kidney involvement in Fabry disease. Adv Chronic Kidney Dis 2006;13:138-147.

4. Torra R, Tazon-Vega B, Ars E, Ballarin J. Collagen type IV (alpha3-alpha4) nephropathy: from isolated haematuria to renal failure. Nephrol Dial Transplant 2004;19:2429-2432.

5. Gregory MC. The clinical features of thin basement membrane nephropathy. Semin   Nephrol 2005;25:140-145.

For more references from this article, visit our Web site: ww.aakp.org

Answer provided by Stephen Z. Fadem, MD, FACP, FASN. Dr. Fadem serves as a vice president of the AAKP National Board of Directors and is a member of the AAKP Medical Advisory Board. He is a practicing nephrologist in Houston.