Autosomal Recessive Polycystic Kidney Disease: A Fatal Disease
Brief Summary of Disease
“In autosomal recessive polycystic kidney disease (ARPKD), kidney function can be significantly affected by the formation of large fluid filled sacs on the surface of the kidney.”
Kidneys are one of the most crucial organs of the body. Every day, through urine production, they filter out waste, toxins and harmful substances out of our bodies while maintaining fluid balance. If the kidneys malfunction, not only do local problems such as issues with urination arise, but detriment to other organs in the body also occurs. In autosomal recessive polycystic kidney disease (ARPKD), kidney function can be significantly affected by the formation of large fluid filled sacs on the surface of the kidney.1 This condition, known as polycystic kidneys, is present in infants born with ARPKD in addition to a variety of other issues affecting their lungs and liver1. In the past, a large proportion of these infants succumbed to the disease within the first few weeks of life. However, due to advances in medicine and particularly due to facilitated kidney transplants, mortality has been reduced to approximately 30%.1 Amongst Canadian infants, 1 in 20,000 is estimated to be affected by the disease.1 Currently, treatments are often targeted towards symptom management; as such, a better understanding of the disease could shine more light into future directions for research.
“Eventually, the impact of ARPKD on the kidneys and liver can result in end-stage renal and hepatic disease. ”
Etiology & Pathology
ARPKD is caused by a mutation of the PKHD1 (polycystic kidney and hepatic disease 1) gene, which codes for a protein known as fibrocystin.2 The protein is found in the membrane of cilia, small hair-like extensions in the membrane of tubes in the kidney, which are crucial for fluid movement.2 The disease is passed on in an autosomal recessive manner , meaning that in order for a child to have the disease, at least one copy of the gene must be mutated in both parents.2 Provided that both parents are carriers of the mutation, there is a 25% chance that their child would have ARPKD. Heterozygous carriers of the disease (those with only one chromosome with the mutated gene) have no disease characteristics but have a higher chance of developing liver disease.2
As the disease is genetic, symptoms begin to manifest early, even affecting proper fetal development. Symptoms arise from cysts formed within the nephrons, tubes in the kidney which filter blood for the production of urine. Over time, the number of functioning nephrons can decrease, culminating in complete absence of kidney function. Eventually, the impact of ARPKD on the kidneys and liver can result in end-stage renal and hepatic disease. At this stage, organ transplantation is often the only possible treatment. 3
“In children and adolescents, kidneys might shrink in size but the liver fibrosis becomes more serious.”
Symptoms
A common misconception is that ARPKD is a fatal disease in all cases. The disease actually has a variable presentation, ranging from mild to severe characteristics with some patients never developing certain symptoms. The formation of cysts in the nephrons, the major symptom of the disease, begin in the fetus, resulting in abnormally large kidneys.4 The cysts themselves can lead to other conditions such as high blood pressure.4
In infants with severe disease, enlarged kidneys during pregnancy inhibit proper development of the lungs and lead to dangerous respiratory conditions. 4 Additionally, improper functioning of the kidneys may interfere with urine production, decreasing the levels of amniotic fluid in the uterus. Low amniotic fluid levels can further amplify respiratory complications during pregnancy. 4
As mentioned before, the liver is another organ heavily impacted by PKHD1 mutations. In most patients, a liver condition called hepatic fibrosis is observed.
4
In this condition, excessive connective tissue forms throughout the liver, resulting in fibrosis. Although liver dysfunction doesn’t develop in all children with the disease, liver abnormalities such as unusual enlargement and inflammation of the ducts connected to the liver can occur.
4
Most infants now survive the neonatal period with the aid of medications. Nevertheless, the symptoms of the disease continue to worsen over time. In children and adolescents, kidneys might shrink in size but the liver fibrosis becomes more serious. 4 Additionally, approximately 50% of patients will end up developing end-stage renal disease in which the kidneys completely lose their function. At this stage, the patients require either kidney transplants or regular dialysis, a procedure in which a machine carries out the function of the kidneys in balancing waste in the body. 4
“If the testing is performed early enough, the disease can be detected prior to cyst formation in the fetus. This could presumably prevent the onset of respiratory complications in the fetus, saving their life. ”
Diagnosis
As the main manifestation of the disease is the presence of enlarged polycystic kidneys, the detection of this symptom by imaging techniques, such as ultrasound, is primarily used for diagnosis in infants.1 Other imaging techniques, such as CT scans which use X-rays for visualization can be used to further confirm the diagnosis.1 Another form of PKD, called autosomal dominant PKD has a very similar presentation to ARPKD if developed in infants.2 As such, to determine which of the two types of PKD an infant has, molecular genetic testing needs to be performed as well.2 If mutations are found in the PKHD1 gene, the infant is confirmed to have ARPKD.2 While on the other hand, if mutations are discovered in PKD1/PKD2, the disease is ADPKD.2 If the testing is performed early enough, the disease can be detected prior to cyst formation in the fetus. This could presumably prevent the onset of respiratory complications in the fetus, saving their life.
Prognosis
Although the disease can have a variable presentation, most patients are faced with severe kidney and liver abnormalities. Approximately 30% of infants die within their first year of life. The mortality is often caused by respiratory complications ensuing from the disease.1 If the infants survive past the first year, their chances of survival rise significantly, with 85% of the patients surviving. In the case of end-stage disease, if patients can’t receive a kidney transplant, they are at high risk of succumbing to the disease. In 10% of the older patients, liver transplantation may be necessary as well.1
For people living with the disease, some of the common signs are chronic pain, high blood pressure, and problems with urination. 4 To manage the symptoms, in addition to medications, it is recommended to have a healthy and balanced diet with regular exercise. In the case of large cysts, chronic pain in the back or the side of the body can be managed by draining the cyst using a large needle. 4
Children
Due to the autosomal recessive fashion in which ARPKD is transmitted, there is a 25% chance of having an infant with ARPKD if both parents have one copy of the mutated gene and 50% if one of the parents has the disease.1 The disease can be detected in utero using ultrasonography and treatments for respiratory and renal deficiencies can begin soon after birth to prevent infant mortality.
For women with ARPKD, pregnancy is often successful and with little complications. 4 If the mother has high blood pressure and protein is detected in her urine however, the pregnancy must be closely monitored to ensure the infant is receiving enough blood.
Using in vitro fertilization recently has allowed for parents with PKD (or carriers of the mutation) to have healthy children. 4 In this method, preimplantation genetic diagnosis is performed on embryos in the lab to allow only healthy embryos to be selected for implantation.
Current Research
“A novel compound trademarked under the name, Tesevatinib, was proposed and found to be effective in diminishing both kidney and liver abnormalities and reducing mortality in mouse models of the disease.”
In a research study by Sweeney et. al, it was demonstrated that increased activity of a receptor in the membrane of cells, called the epidermal growth factor receptor (EGFR), results in the accelerated formation of kidney cysts and liver fibrosis.5 As a result, it was hypothesized that inhibition of EGFR activity could be used to treat ARPKD.5 A novel compound trademarked under the name, Tesevatinib, was proposed and found to be effective in diminishing both kidney and liver abnormalities and reducing mortality in mouse models of the disease.5
The drug has now moved on to phase I clinical trials to determine its safety and efficacy for the treatment of ARPKD.
6
In this clinical trial, which was completed in September 2019, pediatric patients were all administered the drug in different doses.6 Provided that the drug is successful in treating the disease, this would pave the way for future targeted therapies and a more hopeful future for patients diagnosed with autosomal recessive polycystic kidney disease.
Niki Esfahanian
Relevant Resources
The Kidney Foundation of Canada: A national organization with the intention to raise funds and support for research, raise awareness and promote better access to health care for individuals with kidney disease.
An organization based in British Columbia with plans to coordinate better health care for patients.
Works Cited
1. Sweeney WE, Avner ED. Polycystic Kidney Disease, Autosomal recessive. GeneReviews; 2019. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301501.
2. Bergmann C. Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses. Front Pediatr. 2018;5:221. doi:10.3389/fped.2017.00221
3. Martinez JR, Grantham JJ. Polycystic kidney disease: Etiology, pathogenesis, and treatment. Disease-a-Month. 1995;41(11):693-765. doi:10.1016/S0011-5029(05)80007-0
4. Autosomal Recessive Polycystic Kidney Disease [Internet]. Natl Organ Rare Disord. Available from: https://rarediseases.org/rare-diseases/autosomal-recessive-polycystic-kidney-disease/. Published 2016.
5. Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor11. Kidney Int. 2000;57(1):33-40. doi:10.1046/j.1523-1755.2000.00829.x
6. Kadmon Corporation L. A Safety, Pharmacokinetic, Single Ascending Dose Study of Tesevatinib in Pediatric Subjects with Autosomal Recessive Polycystic Kidney Disease (ARPKD)[Internet]. https://clinicaltrials.gov/ct2/show/NCT03096080?cond=ARPKD&draw=2&rank=1.
Cite This Article:
Esfahanian N., Huicochea-Munoz M., Rashid SS., Chan G. Autosomal Recessive Polycystic Kidney Disease: A Fatal Disease. Illustrated by C. Qian. Rare Disease Review. September 2020.
DOI:10.13140/RG.2.2.36056.72962
