autosomal dominant polycystic kidney disease autosomal dominant polycystic kidney disease autosomal dominant polycystic kidney disease (adpkd) 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. autosomal dominant polycystic kidney diseaseother namesautosomal dominant pkd, adult-onset pkdpolycystic kidneysspecialtymedical genetics signs and symptoms among the clinical presentation are: acute loin pain blood in the urine ballotable kidneys subarachnoid hemorrhage (berry aneurysm) hypertension associated liver cysts uremia due to kidney failure anemia due to chronic kidney disease increase rbc or erythropoietin secretion signs and symptoms of adpkd often develop between 30 and 40 years of age. genetics adpkd is genetically heterogeneous with two genes identified: pkd1 (chromosome region 16p13.3; around 85% cases) and pkd2 (4q21; around 15% cases). several genetic mechanisms probably contribute to the phenotypic expression of the disease. although evidence exists for a two-hit mechanism (germline and somatic inactivation of two pkd alleles) 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 (mean age of onset of end-stage renal disease: 54·3 years with pkd1; 74·0 years with pkd2). 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 life. 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 (with the exception of intercalated cells) 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 that lead to cystogenesis are two hallmark features in 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 (camp). 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 (tkv) 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. 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 provide presumptively, but not definite, 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 aneurysm. 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. adult polycystic kidney diagram of autosomal dominant polycystic disease with a normal kidney inset for comparison abdominal ct scan of an adult with autosomal dominant polycystic kidney disease: extensive cyst formation is seen over both kidneys, with a few cysts in the liver, as well. (coronal plane) treatment currently, the only pharmacological treatment available for adpkd consists in reducing the speed in gain of total kidney volume (tkv) with vasopressin receptor 2 (v2) antagonists (i.e. tolvaptan). tolvaptan treatment does not halt or reverse disease progression and patients still progress towards renal failure. palliative treatment modalities involve symptomatic medications (nonopioid and opioid analgesics) for abdominal/retroperitoneal pain. options for analgesic-resistant pain include simple or complex surgical procedures (i.e. renal cyst aspiration, cyst decortication, renal denervation and nephrectomy), which can result in complications inherent to surgery. recent research suggests that ketogenic dietary interventions beneficially affect the progression and symptoms in individuals with adpkd. mild weight loss favorably affects pain indicating the benefit of dietary and lifestyle changes. aquaretic medication in 2014, japan was the first country in the world to approve a pharmacological treatment for adpkd followed by canada and europe, which approved the drug tolvaptan for adpkd patients in the beginning of 2015. the usa fda approved the use of tolvaptan in the treatment of adpkd in 2018. tolvaptan, an aquaretic drug, is a vasopressin receptor 2 (v2) antagonist. pre-clinical studies had suggested that the molecule camp could be involved in the enlargement of adpkd cysts, and studies on rodents confirmed the role of vasopressin in increasing the levels of camp in the kidney, which laid the basis for the conduction of clinical studies. because data from the consortium for radiologic imaging studies of polycystic kidney disease (crisp) led by mayo clinic showed that total kidney volume (tkv) predicted the risk of developing chronic kidney disease in patients with adpkd, the tempo 3:4 trial, which enrolled patients from 129 sites worldwide from 2007 to 2009, evaluated tkv as a primary end-point to test the efficacy of tolvaptan in adpkd patients. that study showed a significant decrease in the ratio of tkv increase and deterring of renal function decline in adpkd patients after treatment with tolvaptan; however, because laboratory test results regarding liver function appeared elevated in a percentage of patients enrolled in that study, the approval of the drug was either delayed by regulatory agencies or, as in case of the us, altogether denied. dietary and lifestyle interventions research using adpkd mouse models showed that mild food restriction strongly improved disease progression. the mechanism was shown to involve the metabolic state of ketosis, and beneficial effects could be produced by time-restricted feeding, acute fasting, a ketogenic diet, or by supplementation with the ketone beta-hydroxybutyrate in mouse, rat and cat models of adpkd. a ketogenic diet regimen not only halted further disease progression but led to partial reversal of renal cystic disease in a rat model. the metabolic state of ketosis may be beneficial in adpkd because renal cyst cells in adpkd have a metabolic defect similar to the warburg effect in cancer that makes them highly dependent on glucose, and unable to metabolize fatty acids and ketones. consistent with this, serum glucose levels positively correlate with faster disease progression in adpkd patients. also, individuals with adpkd and type 2 diabetes have significantly larger total kidney volume (tkv) than those with adpkd alone, and overweight or obesity associate with faster progression in early-stage adpkd. a retrospective case series study showed that adpkd disease symptoms - including pain, hypertension and renal function - improved among 131 patients who implemented ketogenic diets for an average duration of 6 months. dietary intake of sodium is associated with worse renal function decline in adpkd, and limiting sodium intake is generally recommended to patients. dietary protein intake was not found to correlate with adpkd progression. increased water intake is thought to be beneficial in adpkd and is generally recommended. the underlying beneficial mechanism of increased water intake may be related to effects on the vasopressin v2 receptor or may be due to the suppression of harmful micro-crystal formation in renal tubules by dilution of solutes such as calcium oxalate, calcium phosphate and uric acid. dietary intake of oxalate or inorganic phosphate has been shown to accelerate pkd disease progression in several rodent models. low levels or urinary citrate – a natural antagonist of the formation of harmful crystals in kidney tubules – have been shown to associate with worse disease progression in adpkd patients. analgesic medication chronic pain in patients with adpkd is often refractory to conservative, noninvasive treatments, but nonopioid analgesics and conservative interventions can be first used before