Poly cystic Kidney Disease: Genetic and Pathogenesis

Poly cystic Kidney Disease: Genetic and Pathogenesis

Introduction to Polycystic Kidney Disease

As the name suggests, polycystic kidney disease (PKD) is a condition characterized by the formation and growth of cysts in the kidney. This disease is a genetic disorder with two different types. The first is autosomal dominant polycystic kidney disease (ADPKD) and is the more common of the two. The second type is autosomal recessive polycystic kidney disease (ARPKD), which is much rarer (Crow, 2017). Being a genetic disorder, PKD can be assumed to have existed throughout human history. However, it was encountered and observed medically in 1586, with the death of the King of Poland, Stephen Bathory. After his death, his Surgeon Jan Zigulitz recorded that the king’s kidneys were large as a bull, with a bumpy and uneven surface. In the 18th century, doctors and historians reading these records concluded that PKD must have been the cause of his death. The term “polycystic kidney” was first used in 1888 by Flix Lejars, who characterized the disease as affecting both kidneys, and having clear and specific symptoms. In 1994, the disease was discovered to have a cause that was genetic in nature, with around 85% of ADPKD patients possessing the PKD-1 gene on chromosome 16 (Balat, 2016).Poly cystic Kidney Disease: Genetic and Pathogenesis

ADPKD affects around 4. 3 per 10, 000 people, or 0. 043% of the population. It is almost twice as likely for women to be diagnosed in early adulthood because of their receiving of ultrasound testing during childbearing years. On the other hand, males are commonly diagnosed at the 65 years and older demographic, indicating that there is greater possibility for ADPKD to be undiagnosed in young men. In the United States, ADPKD affects about 140, 000 patients, making it a relatively rare disease. On the other hand, ARPKD affects 1 in 20, 000 to 40, 000 people (Willey et al., 2019). PKD will not cause signs or symptoms while the cysts are small. Thus, PKD will be difficult to detect without being tested. Once the cysts are 0. 5 inches or larger, symptoms will begin to manifest themselves. Symptoms include high blood pressure, blood in urine, excessive urination, headaches, and pain in the abdominal area or in the back. Furthermore, this condition will lead to the formation of clusters of cysts in the kidney and potentially other organs like the liver, pancreas, and testes. PKD is also associated with aneurysms in the arteries or the brain, and diverticula of the colon (Phillips, 2018). Generally, the only risk factor for this disease is having inherited this gene from one’s parents or grandparents. However, it is possible for this disease to occur without parents carrying the mutation due to a mutation occurring in the embryonic development process. (Iliuta et al., 2017)


PKD is an inherited disease that is caused by mutations occurring in the genes, that have been inherited from one’s parents. In ADPKD, 85% of cases have the mutation occurring in the PKD1 gene, located on chromosome 16p13. 3. In the remaining 15% of cases, the mutation occurs in the PKD2 gene, located on chromosome 4q21-23. The PKD1 gene codes for the protein polycystin-1 (Igarashi & Somlo, 2002). This protein contains a long extracellular N-terminal portion and eleven transmembrane domains. The extracellular portion contains multiple domains, including two leucine-rich repeat areas, that are able to bind collagen, fibronectin, and laminin. The protein also may be able to bind carbohydrates and the protein-ligand. The PKD2 gene codes for the protein polycystin-2. In ADPKD, all the cells in the kidney carry the mutated gene, but only some of the nephrons (the kidney’s functional subunit) present cysts, with each nephron having a few cysts. Thus, ADPKD is a focal disease that does not impact all of the kidney’s nephrons equally (Walker, Mojares, & Hernández, 2018).Poly cystic Kidney Disease: Genetic and Pathogenesis


While the exact mechanism of cyst formation is not understood, the focal nature of the disease has caused researchers to suggest a two-hit model (Qian et al., 1996). This model begins with the assumption that an individual with ADPKD has inherited a mutated PDK1 or PDK2 gene from one parent, and a wild-type gene from the other parent. The model theorizes that the wild-type gene then becomes inactivated during the individual’s lifetime, due to a somatic mutation. These somatic mutations are mutations that happen in adult fully formed cells when are then passed on to successive generations of cells. As somatic mutations happen infrequently, the formation of cysts will also be irregular, and only localized to specific nephrons in the kidney. This theory is supported by studies showing that renal cysts have lost their wild-type allele and are no longer heterozygous. If this theory is true, then it must also account for the large number of cysts that exist in the later stages of polycystic kidneys. This can be accounted for by studies observing the rate of somatic mutations in kidney epithelial cells is ten times higher than the rate in other cells (Colgin et al., 2002).

While the reason for the difference in mutation rate is unknown, it does explain how the high incidence of mutation could be possible. Polycystin-1, the product of the PK1 gene, is a protein that regulates the cell cycle, and the unregulated proliferation of the cell may be one factor leading to vesicle fusion, and eventually cyst formation. Polycystin-2, the product of the PK2 gene, protein that functions as an intracellular calcium release channel (González-Perrett et al., 2001). The mutation in the calcium channel causes the rise of calcium in the cytosol, which can lead to vesicle fusion and changes in the transcription of genes, and eventually cyst formation. Although the products of the PK1 and PK2 genes are different, the fact that they interact in the same pathway gives an explanation for why they both result in the same result of cyst formation (Qian et al., 1996).

The presence of cysts in PKD hinders the kidneys from their function of filtering waste products in the blood. While each cyst itself is not tremendously dangerous, the high number of steadily growing cysts harms the body by impacting the kidneys at a mechanical level. This can lead to high blood pressure, blood in the urine, and pain in the kidney area felt as emanating from the back or sides. Compared to a healthy kidney, a polycystic kidney will be enlarged, riddled with up to thousands of cysts, and severely lacking in function. PDK can also be accompanied by cysts in the liver, or other organs (‘Kidney Cyst | Polycystic Kidney Disease’, 2019).Poly cystic Kidney Disease: Genetic and Pathogenesis

Treatment and Research

There is currently no cure for autosomal dominant polycystic kidney disease (ADPKD), and it is not possible to stop cysts forming in the kidneys for those who have been diagnosed with the disease. However, as ADPKD progresses slowly, there is a window of opportunity to treat the disease by retarding cystic expansion. On Tuesday, April 24, 2018, the U. S. Food and Drug Administration granted approval of tolvaptan for ADPKD treatment, the first medication of its kind for this disease. This medication has also received a recommendation from the National Institute for Health and Care Excellence for ADPKD treatment (‘Approved as First Treatment for ADPKD’). Tolvaptan interacts with arginine vasopressin, a hormone that promotes the reabsorption of water from the fluid in the kidney’s tubules into the collecting duct. Tolvaptan is an arginine vasopressin antagonist, hindering this hormone’s ability to function. The precise mechanism is to block vasopressin-2 receptors in the collecting duct of the kidney. In doing this, it increases the excretion of free water while maintaining the kidney’s functionality.

The result is that the formation of cysts in the kidney is slowed (Bhatt et al., 2014). By reducing the rate of cyst growth, tolvaptan reduces ADPKD’s kidney growth and enables longer preservation of kidney function. However, tolvaptan is only available to adults who have chronic kidney disease (at stage 3 or 4) at the start of their treatment, when there evidence of rapidly progressing kidney disease. Tolvaptan is given as a tablet, which is taken twice per day. The side effects of tolvaptan are primarily related to the frequency of urination. Thus, tolvaptan causes side effects like thirst, the urination of at least 3 liters per day (polyuria), and the need to pee more than 5 times at daytime (pollakiuria) and once at night (nocturia). Another more severe negative side effect of tolvaptan is chemical-related liver damage (hepatotoxicity), which has also been reported in a number of patients. Thus, taking tolvaptan must be accompanied by frequent monitoring (‘Treatment: Autosomal dominant polycystic kidney disease’, 2019).Poly cystic Kidney Disease: Genetic and Pathogenesis

Prior to the availability of tolvaptan as a means of treatment, treatment involved seeking to address the various health complications arising from ADPKD. For example, ADPKD can lead to high blood pressure, kidney stones, and localized pain. While ADPKD itself could not be treated, treatment focused on addressing these symptoms. Of these symptoms, hypertension is the most common. ADPKD can also lead to the experience of back or side pain due to the enlargement of the kidneys, or pain due to kidney stones. In these cases, the practice is to avoid the use of ibuprofen and other non-steroidal anti-inflammatory drugs. This is because such drugs can raise one’s blood pressure, and work against the drugs being taken to reduce blood pressure. Instead, painkiller drugs like paracetamol, codeine, or tramadol are given. Chronic pain can also be treated with the use of antidepressants. In terms of surgical treatment, large cysts can be drained in order to release pain from pressure and reduce kidney enlargement (‘Treatment: Autosomal dominant polycystic kidney disease’, 2019).

As the disease progresses, the patient’s kidney functionality will be regularly observed. As the kidneys approach kidney failure, the patient has two options of treatment. The first option is to regularly give them dialysis, which is the process in which a machine replicates some of your kidneys’ functions, filtering the body’s blood. Dialysis generally is administered in four-hour sessions, three times a week. The other option of treatment is to receive a kidney transplant, which is the removal of the diseased kidney and the implantation of a healthy donated kidney. For implanted kidneys, as they do not share the genetic phenotype of the ADPKD/ARPKD individual, they do not develop cysts. These transplants can come from either deceased donors, or from a donated kidney, possibly from a blood relative. Receiving a kidney transplant dramatically increases the quality of life that a PKD individual will experience when compared to having to receive regular dialysis (‘Treatment: Autosomal dominant polycystic kidney disease’, 2019).

Article Critique

The article chosen for this assignment is “Genetics and Pathogenesis of Polycystic Kidney Disease” by Peter Igarashi and Stefan Somlo, published in the Journal of American Society of Nephrology. This article is excellent in its comprehensive nature, as it explains the disease in. The article begins with a general explanation of PKD as a disease and the nature of the cysts that are formed in the kidney. It also provides a concise explanation of the genetic nature of this disease and the dominant and recessive forms that it takes. Overall, the beginning of the article is accessible enough for anyone unfamiliar with this disease to get a basic grasp of the disease, its genesis, and its symptoms.Poly cystic Kidney Disease: Genetic and Pathogenesis

This article is also strong in its clarity. Although it addresses a potentially complex topic, its accessibility is increased in that it takes a logical progression that increases in complexity. After a simple intro, it explores the genetics of the disease. It then describes the focal nature of the disease and presents a two-hit model of how cysts are formed. It gives the confirmation of this hypothesis in mice models. The article then progresses into a more complex and technical portion, exploring the disease at the gene and protein interaction level. It does this for the ADPKD specifics of the disease and then begins to address the detailed interactions for the ARPKD expressive of the disease. In the latter portion of the article, it addresses the involvement of cilia in PDK. Another strength of this article is that it seeks to give as much explanation of the disease at the protein level, despite the fact that much of the details of PKD are unknown. This article closes with the presentation of cilia as a potential target of treatment, which is a helpful but brief conclusion.

One of the weaknesses of this article is that it is dated. Being published in 2002, there has been much development in the science of PKD, especially the development of tolvaptan as treatment, and its FDA approval in 2016. Thus, this article is an excellent resource in understanding the disease and its underlying causes and protein interactions. However, in order to gain an understanding of the current science of this disease, this article should be complemented with articles from the past five years.Poly cystic Kidney Disease: Genetic and Pathogenesis

The post Poly cystic Kidney Disease: Genetic and Pathogenesis appeared first on Nursingfy.

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