Аутосомно-доминантная поликистозная болезнь почек: генетика, патогенез и вариабельность

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. 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.

ADPKD is genetically heterogeneous with two genes identified: PKD1 (chromosome region 16p13.3; around 85% cases) and PKD2 (4q21; around 15% cases). 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. 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.

In many patients with ADPKD, kidney dysfunction is not clinically apparent until 30 or 40 years of life. Cysts initially form as small dilations in renal tubules, which then expand to form fluid filled cavities of different sizes. 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.

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; 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.

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.

In 2014, Japan was the first country in the world to approve a pharmacological treatment for ADPKD Tolvaptan, an aquaretic drug, is a vasopressin receptor 2 (V2) antagonist. 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. 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.

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. 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. 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.

Aspiration with ethanol sclerotherapy can be performed for the treatment of symptomatic simple renal cysts, but can be impractical in advanced patients with multiple cysts. The procedure itself consists in the percutaneous insertion of a needle into the identified cyst, under ultrasound guidance, with subsequent draining the contained liquid; the sclerotherapy is used to avoid liquid reaccumulation that can occur in the cyst, which can result in symptom recurrence.

Laparoscopic cyst decortication (also referred to as marsupialization) consists in the removal of one or more kidney cysts through laparoscopic surgery, during which cysts are punctured, and the outer wall of the larger cysts is excised with care not to incise the renal parenchyma. This procedure can be useful for pain relief in patients with ADPKD, and is usually indicated after earlier cyst aspiration has confirmed that the cyst to be decorticated is responsible for pain. Laparoscopic decortication presents a 5% recurrence rate of renal cysts compared to an 82% recurrence rate obtained with sclerotherapy. This involves the chemical ablation of the celiac plexus, to cause a temporary degeneration of targeted nerve fibers. When the nerve fibers degenerate, it causes an interruption in the transmission of nerve signals. This treatment, when successful, provides significant pain relief for a period ranging from a few days to over a year. The procedure may be repeated when the affected nerves have healed and the pain returns.

Many ADPKD patients experience symptomatic sequelae in consequence of the disease, such as cyst hemorrhage, flank pain, recurrent infections, nephrolithiasis, and symptoms of mass effect (i. e., early satiety, nausea and vomiting, and abdominal discomfort), from their enlarged kidneys. In such cases, nephrectomy can be required due to intractable symptoms or when in the course of preparing for kidney transplantation, the native kidneys are found to impinge upon the true pelvis and preclude the placement of a donor allograft. Additionally, native nephrectomy may be undertaken in the presence of suspected malignancy, as renal cell carcinoma (RCC) is two to three times more likely in the ADPKD population in end stage kidney disease (ESKD) than in the ESKD patients without ADPKD. Although the indications for nephrectomy in ADPKD may be related to kidney size, the decision to proceed with native nephrectomy is often undertaken on an individual basis, without specific reference to kidney size measurements. Epidemiological data shows that ADPKD affects 5–13.4% of patients undergoing hemodialysis in Europe and in the United States, and about 3% in Japan. however, no difference is seen in long term morbidity between hemodialysis and peritoneal dialysis in ADPKD.

In ADPKD patients, gradual cyst development and expansion result in kidney enlargement, and during the course of the disease, glomerular filtration rate remains normal for decades before kidney function starts to progressively deteriorate, making early prediction of renal outcome difficult. The CRISP study,