Autosomal dominant polycystic kidney disease


Autosomal dominant polycystic kidney disease is one of the most common, life-threatening inherited human disorders and the most common hereditary kidney disease. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. It is also the most common of the inherited cystic kidney diseases — a group of disorders with related but distinct pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations, which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles, pancreas, and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, and abdominal wall hernias. Over 50% of patients with ADPKD eventually develop end stage kidney disease and require dialysis or kidney transplantation. ADPKD is estimated to affect at least one in every 1000 individuals worldwide, making this disease the most common inherited kidney disorder with a diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.

Signs and symptoms

ADPKD can result in a wide variety of clinical symptoms. Symptoms may be caused directly by a cyst growing or bursting, or indirectly due to problems with other physiological functions. Most symptoms occur around 40 years of age, but some clinical symptoms can occur decades prior to the development of over kidney disease, with some symptoms presenting as early as childhood.
Primary Symptoms Include:
  • Early-onset hypertension
  • Blood in urine
  • Abdominal, flank, or back pain
  • Masses in the abdomen or flank
  • Decrease in renal function
Among the most common symptoms associated with it is early-onset hypertension. Early-onset hypertension is present in 50%-70% of individuals with ADPKD. Hypertension can even develop before the decline in kidney function markers like GFR.
The presence of ADPKD is associated with several extra-renal symptoms, including the development of cysts in organs outside of the kidney. Polycystic liver disease is often found in adults with ADPKD and can be present in greater than 90% of individuals with ADPKD over 35 years old. Polycystic liver disease develops more often in females with ADPKD than males, with risk factors including and exposure to non-endogenous sources of estrogen and multiple gestations. Individuals with polycystic liver disease due to ADPKD can also experience gastrointestinal symptoms related to the presence of cysts in the liver, such as early discomfort, fullness, and gastroesophageal reflux. In rare cases, portal hypertension with secondary ascites and pleural effusion can also occur.
Individuals with ADPKD are also at increased risk for developing intracranial aneurysms. The risk of intracranial aneurysms is estimated to be four times higher in people with ADPKD when compared to the general population, and as a result, screening with magnetic resonance angiography is recommended for high-risk populations.
Additionally, symptoms such as abdominal fullness, excessive urination, and recurring urinary tract infections, kidney stones, and bladder infection are also associated with ADPKD.
ADPKD can also result in a wide array of symptoms beyond the kidneys, resulting in the following symptoms:
  • Neurological: Arachnoid cysts, intracranial hemorrhage.
  • Cardiovascular: Pericardial effusion, mitral valve prolapse, bicuspid aortic valve
  • Endocrine: Pancreatic cysts
  • Gastrointestinal: Polycystic liver disease, diverticulosis
  • Pulmonary: Bronchiectasis
  • Reproductive: Male infertility, seminal vesicle cysts, ovarian cysts
Among the clinical presentation are:
Signs and symptoms of ADPKD often develop between 30 and 40 years of age.

Genetics

ADPKD is genetically heterogeneous with two genes identified: PKD1 and PKD2. Several genetic mechanisms probably contribute to the phenotypic expression of the disease. Although evidence exists for a two-hit mechanism explaining the focal development of renal and hepatic cysts, haploinsufficiency is more likely to account for the vascular manifestations of the disease. Additionally, new mouse models homozygous for PKD1 hypomorphic alleles 22 and 23 and the demonstration of increased renal epithelial cell proliferation in PKD2 +/− mice suggest that mechanisms other than the two-hit hypothesis also contribute to the cystic phenotype.
Large interfamilial and intrafamilial variability occurs in ADPKD. Most individuals with PKD1 mutations have kidney failure by age 70 years, whereas more than 50% of individuals with PKD2 mutations have adequate renal function at that age.
The significant intrafamilial variability observed in the severity of renal and extrarenal manifestations points to genetic and environmental modifying factors that may influence the outcome of ADPKD, and results of an analysis of the variability in renal function between monozygotic twins and siblings support the role of genetic modifiers in this disease. It is estimated that 43–78% of the variance in age to ESRD could be due to heritable modifying factors, with parents as likely as children to show more severe disease in studies of parent-child pairs.

Pathophysiology

In many patients with ADPKD, kidney dysfunction is not clinically apparent until 30 or 40 years of age. However, an increasing body of evidence suggests the formation of renal cysts starts in utero. Cysts initially form as small dilations in renal tubules, which then expand to form fluid-filled cavities of different sizes. Factors suggested to lead to cystogenesis include a germline mutation in one of the polycystin gene alleles, a somatic second hit that leads to the loss of the normal allele, and a third hit, which can be a renal insult that triggers cell proliferation, and an injury response. Due to numerous similarities between the pathophysiology of ADPKD and the pathophysiology of the renal response to injury, ADPKD has been described as a state of aberrant and persistent activation of renal injury response pathways. In the progression of the disease, continued dilation of the tubules through increased cell proliferation, fluid secretion, and separation from the parental tubule lead to the formation of cysts.
ADPKD, together with many other diseases that present with renal cysts, can be classified into a family of diseases known as ciliopathies. Epithelial cells of the renal tubules, including all the segments of the nephron and the collecting ducts show the presence of a single primary apical cilium. Polycystin-1, the protein encoded by the PKD1 gene, is present on these cilia and is thought to sense the flow with its large extracellular domains, activating the calcium channels associated with polycystin-2, the product of gene PKD2, as a result of the genetic setting of ADPKD as explained in the genetics sub-section above.
Epithelial cell proliferation and fluid secretion lead to cystogenesis, which are two hallmark features of ADPKD. During the early stages of cystogenesis, cysts are attached to their parental renal tubules and a derivative of the glomerular filtrate enters the cysts. Once these cysts expand to approximately 2 mm in diameter, the cyst closes off from its parental tubule and after that fluid can only enter the cysts through transepithelial secretion, which in turn is suggested to increase due to secondary effects from an increased intracellular concentration of cyclic AMP.
Clinically, the insidious increase in the number and size of renal cysts translates as a progressive increment in kidney volume. Studies led by Mayo Clinic professionals established that the total kidney volume in a large cohort of ADPKD patients was 1060 ± 642ml with a mean increase of 204ml over three years, or 5.27% per year in the natural course of the disease, among other important, novel findings that were extensively studied for the first time.
Image:PKD1PKD2 en.png|thumb|Illustration of PKD1 and PKD2 proteins at the cell membrane

Diagnosis

Usually, the diagnosis of ADPKD is initially performed by renal imaging using ultrasound, CT scan, or MRI. However, molecular diagnostics can be necessary in the following situations: 1- when a definite diagnosis is required in young individuals, such as a potential living related donor in an affected family with equivocal imaging data; 2- in patients with a negative family history of ADPKD, because of potential phenotypic overlap with several other kidney cystic diseases; 3- in families affected by early-onset polycystic kidney disease, since in this cases hypomorphic alleles and/or oligogenic inheritance can be involved; and 4- in patients requesting genetic counseling, especially in couples wishing a pre-implantation genetic diagnosis.
The findings of large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD are diagnostic. In the absence of a family history of ADPKD, the presence of bilateral renal enlargement and cysts, with or without the presence of hepatic cysts, and the absence of other manifestations suggestive of a different renal cystic disease provides presumptively, but not definitively, evidence for the diagnosis. In some cases, intracranial aneurysms can be an associated sign of ADPKD, and screening can be recommended for patients with a family history of intracranial aneurysms.
Molecular genetic testing by linkage analysis or direct mutation screening is clinically available; however, genetic heterogeneity is a significant complication to molecular genetic testing. Sometimes, a relatively large number of affected family members need to be tested in order to establish which one of the two possible genes is responsible within each family. The large size and complexity of PKD1 and PKD2 genes, as well as marked allelic heterogeneity, present obstacles to molecular testing by direct DNA analysis. The sensitivity of testing is nearly 100% for all patients with ADPKD who are age 30 years or older and for younger patients with PKD1 mutations; these criteria are only 67% sensitive for patients with PKD2 mutations who are younger than age 30.