Genetic Diseases

 Polycystic kidney disease (PKD or PKR, also known as polycystic kidney syndrome) is a cystic genetic kidney disease.

   The disease occurs in humans and many animals. PKD is characterized by the presence of multiple cysts (hence, "polycystic kidney disease") in both kidneys. The number of cysts is numerous and their fluid-filled nature leads to a significant enlargement of the kidneys. The disease can also lead to damage to the liver, pancreas, and in some rare cases, heart and brain. The two main forms of polycystic kidney disease differ in the type of inheritance.

  

   Polycystic kidney disease is the most common genetic, life-threatening disease affecting more than 600,000 Americans and about 12.5 million people worldwide.

  

Types of inheritance

 

Autosomal dominant type of inheritance

 

    AD-PKD is a severe disease characterized by the progressive development of cysts and bilateral enlargement of the kidney with multiple cysts. This is a genetic disease that occurs as a result of mutations in either the PKD-1 or PKD-2 gene. Cysts begin to form in the womb from anywhere along the nephron, although <5% of the total number of nephrons are considered to be involved in the pathological process. As the cysts accumulate fluid, they grow larger, completely separating from the nephron, compressing the adjacent renal parenchyma, which gradually jeopardizes renal function.

 

     ADPKD occurs in 1:400-1:1000 people worldwide and accounts for approximately 4% of chronic kidney disease (CKD). In more than 90% of cases, the disease is inherited as an autosomal dominant trait characterized by spontaneous mutations. Mutations in the CKD-1 gene on chromosome 16 (ADPKD-1) account for 85% of cases, while mutations in the CKD-2 gene on chromosome 4 (ADPKD-2) represent the remainder. It so happened that several families had a defect at a site different from any of these loci. Direct analysis of mutations in isolated cysts suggests that there is a loss of heterozygosity, where somatic mutations in normal wild-type alleles of a small number of renal tubules lead to unregulated cell proliferation, which ultimately forms cysts.

 

Clinical manifestations

 

     Symptoms and signs of the disease include abdominal discomfort, hematuria, urinary tract infection, sudden onset of hypertension, abdominal masses, increased blood creatinine, or cystic vesicles in the early stages. As a rule, patients experience renal pain, and later develop renal failure.

 

     Approximately 50% of patients with AD-PKD have chronic kidney disease with chronic renal failure (CKD) before the age of 60, but those with ADPKD-2 tend to have a later onset and slower progression of the disease. Hypertension is common, often preceding renal dysfunction. Common clinical manifestations of renal enlargement are abdominal pain, early satiety, and gastroesophageal reflux symptoms. Cyst rupture or hemorrhage into the cyst can lead to acute pain or symptoms and signs of local peritonitis. Hematuria can occur as a result of a cyst rupturing into the urinary system or the presence of uric acid or calcium oxalate stones in the kidneys. Urolithiasis occurs in about 20% of patients.

 

      Urinary tract infections occur with increased frequency in ADPKD. Infections in the kidney or liver cysts are a particularly serious complication. This is most often caused by gram-negative bacteria and is accompanied by pain, fever, and chills. Hemoculture or simply the presence of bacteria in the urine is often positive, but the urine sample may be negative, as often infected kidney cysts do not directly contact the urinary system. Distinguishing between infection and cyst bleeding is often a challenge, and the diagnosis is based primarily on clinical and bacteriologic findings. Radiological and nuclear studies are usually not useful.

 

     Risk factors for progressive renal disease are young age at diagnosis, black race, male gender, the presence of a mutation in PCN-1, and hypertension.

 

     Numerous extrarenal manifestations of ADPKD emphasize the systemic nature of the disease and probably reflect generalized abnormalities in collagen and extracellular matrix. Patients with ADPHN have an increased risk of hemorrhagic stroke due to intracranial aneurysm compared to the general population. Saccular aneurysms of the anterior circulation can be detected in 10% of asymptomatic patients on MRI examination, but most of them are small, have a low risk of spontaneous rupture, and do not require intervention. In general, bleeding usually occurs in patients under 50 years of age with a family history of intracranial hemorrhage. Survivors of previous bleeding develop an aneurysm larger than 10 mm and have uncontrolled hypertension. Other vascular disorders often occur in the ascending aorta. Heart valve dysfunction occurs in 25% of patients, most commonly mitral valve prolapse and aortic valve regurgitation. Although heart valve lesions are asymptomatic, some of them can progress over time and require valve replacement. Abdominal and inguinal hernias in ADPKD are more common than in the general population.

 

Diagnosis

 

      The probability of detecting renal disease by ultrasound reaches 100% for subjects over 30 years of age with a positive family history. Diagnostic criteria require the presence of two or more cysts in one kidney and at least one cyst in the opposite kidney in younger individuals, and four or more cysts in those over 60 years of age due to the increasing incidence of benign simple cysts. Most often, the diagnosis is made from a positive family history and medical imaging, which indicate multiple bilateral cysts in the kidneys and possibly in the liver. Before the age of 30, computed tomography or T2-weighted MRI is more reliable for detecting premature disease, as ultrasound detects ADPKD type 1 in 95% of cases and ADPKD type 2 in less than 70%. After the examination, genetic counseling is necessary. 5% of patients with this disease are likely to develop a cerebral vascular aneurysm.

 

Treatment.

 

      At the moment, research is widely conducted on the treatment of the disease, as there is no single therapy that can prevent the decline in renal function. It is recommended to control hypertension at 130/85 or less. A lower level slows down the rate of loss of kidney function. Often, a drug approach that includes drugs that inhibit the renin-angiotensin system is necessary. There is no convincing evidence that a low-protein diet is a prerequisite for treatment, especially in patients with advanced renal dysfunction, where nutritional optimization is essential. Antimicrobial fat-soluble drugs, such as trimethoprim-sulfamethoxazole and quinolone antibiotics, which effectively penetrate tissues, are a positive therapy for renal cyst infection. Pain relief sometimes requires drainage of the cyst by percutaneous aspiration, sclerotherapy with drainage. Patients with ADPKD usually have a better chance of survival with peritoneal or hemodialysis compared to patients with other forms of CKD. Patients who need a kidney transplant may require both kidneys to be removed if the kidneys are severely enlarged or if the cysts in them are infected. The likelihood of survival after kidney transplantation is similar for patients with other forms of renal failure, but there is still a risk of extrarenal complications of ADPKD for patients.

 

Autosomal recessive type of inheritance

 

In cats

 

      Polycystic kidney disease (PKD) is also widespread in Persian, Himalayan, exotic shorthair, and Norwegian Forest cats.

There are three possible genotypes of PKD:

- 1) N/N (2 copies of normal alleles);

- 2) N/P heterozygotes (1 standard copy and 1 copy of the PCN mutation)

- 3) P/P (2 copies of the PCN mutation)

 

 

      PCN DNA testing is available to detect these genotypes so that cat breeders can make a more informed decision about choosing a mating partner.

 

Potential alternative treatments

 

     There is no cure for the disease. Usually, the need for transplantation arises only after the patient has end-stage renal disease. Studies show that treatment with new tyrosine kinase inhibitor drugs, such as extracts from anthocyanin-rich foods (berries and grapes), can be used in PKD.