Autosomal dominant polycystic kidney disease | |
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Other names | Autosomal dominant PKD, adult-onset PKD |
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Polycystic kidneys | |
Specialty | Medical genetics ![]() |
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening inherited human disorders and the most common hereditary kidney disease. [1] [2] It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. [1] 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. [1] [3] [4] Over 50% of patients with ADPKD eventually develop end stage kidney disease and require dialysis or kidney transplantation. [1] [5] 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. [6] [7] [8] [9] [10]
Among the clinical presentation are:[ citation needed ]
Signs and symptoms of ADPKD often develop between 30 and 40 years of age. [11]
ADPKD is genetically heterogeneous with two genes identified: PKD1 (chromosome region 16p13.3; around 85% cases) [12] and PKD2 (4q21; around 15% cases). [13] [14] [1] Several genetic mechanisms probably contribute to the phenotypic expression of the disease. [1] 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, [15] [16] haploinsufficiency is more likely to account for the vascular manifestations of the disease. [17] [18] 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. [1]
Large interfamilial and intrafamilial variability occurs in ADPKD. [1] 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). [19]
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. [1] [20] It is estimated that 43–78% of the variance in age to ESRD could be due to heritable modifying factors, [21] [22] with parents as likely as children to show more severe disease in studies of parent-child pairs. [1] [23]
In many patients with ADPKD, kidney dysfunction is not clinically apparent until 30 or 40 years of life. [5] However, an increasing body of evidence suggests the formation of renal cysts starts in utero. [24] Cysts initially form as small dilations in renal tubules, which then expand to form fluid-filled cavities of different sizes. [24] 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. [25] 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. [26] 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. [27] [28]
ADPKD, together with many other diseases that present with renal cysts, can be classified into a family of diseases known as ciliopathies. [29] 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. [30] 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, [31] 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. [32] During the early stages of cystogenesis, cysts are attached to their parental renal tubules and a derivative of the glomerular filtrate enters the cysts. [24] 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). [24]
Clinically, the insidious increase in the number and size of renal cysts translates as a progressive increment in kidney volume. [1] [24] 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. [33]
Usually, the diagnosis of ADPKD is initially performed by renal imaging using ultrasound, CT scan, or MRI. [34] 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; [34] 2- in patients with a negative family history of ADPKD, because of potential phenotypic overlap with several other kidney cystic diseases; [34] 3- in families affected by early-onset polycystic kidney disease, since in this cases hypomorphic alleles and/or oligogenic inheritance can be involved; [34] [35] and 4- in patients requesting genetic counseling, especially in couples wishing a pre-implantation genetic diagnosis. [34] [36]
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. [37]
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.[ citation needed ]
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). [38] 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.[ citation needed ] Recent research suggests that ketogenic dietary interventions beneficially affect the progression and symptoms in individuals with ADPKD. [39] Mild weight loss favorably affects pain [40] 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 [33] 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. [41] Tolvaptan, an aquaretic drug, is a vasopressin receptor 2 (V2) antagonist. [9] Pre-clinical studies had suggested that the molecule cAMP could be involved in the enlargement of ADPKD cysts, [42] 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. [43] 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, [33] [44] 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. [9] [10] 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; [9] [45] 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. [10] [46]
Research using ADPKD mouse models showed that mild food restriction strongly improved disease progression. [47] 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. [48] [49] A ketogenic diet regimen not only halted further disease progression but led to partial reversal of renal cystic disease in a rat model. [49] 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. [48] [50] [51] Consistent with this, serum glucose levels positively correlate with faster disease progression in ADPKD patients. [52] Also, individuals with ADPKD and type 2 diabetes have significantly larger total kidney volume (TKV) than those with ADPKD alone, [53] and overweight or obesity associate with faster progression in early-stage ADPKD. [54] 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. [39]
Dietary intake of sodium is associated with worse renal function decline in ADPKD, [55] and limiting sodium intake is generally recommended to patients. Dietary protein intake was not found to correlate with ADPKD progression. [56]
Increased water intake is thought to be beneficial in ADPKD and is generally recommended. [57] [58] 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. [57] [59]
Dietary intake of oxalate or inorganic phosphate has been shown to accelerate PKD disease progression in several rodent models. [57] 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. [57]
Chronic pain in patients with ADPKD is often refractory to conservative, noninvasive treatments, but nonopioid analgesics and conservative interventions can be first used before opioid analgesics are considered; if pain continues, then surgical interventions can target renal or hepatic cysts to directly address the cause of pain, with surgical options including renal cyst decortication, renal denervation, and nephrectomy. [60]
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. [61] 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. [61] [62]
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. [63] [64] 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. [64] Nonrandomised controlled trials conducted in the '90s showed that patients with symptomatic simple renal cysts who had recurrence of symptoms after initial response to simple aspiration could be safely submitted to cyst decortication, with a mean pain-free life between 17 and 24 months after surgery. [63] [65] Laparoscopic decortication presents a 5% recurrence rate of renal cysts compared to an 82% recurrence rate obtained with sclerotherapy. [62]
A novel treatment of specifically the chronic pain experienced by many with ADPKD is Celiac plexus neurolysis. [66] [67] 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. [68]
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. [69] [70] [71] 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. [70] [71] [72] [73] 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. [71] [74] 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. [71]
Two modalities of dialysis can be used in the treatment of ADPKD patients: peritoneal dialysis and hemodialysis. [75] Epidemiological data shows that ADPKD affects 5–13.4% of patients undergoing hemodialysis in Europe and in the United States, [76] [77] [78] and about 3% in Japan. [7] Peritoneal dialysis has usually been contra-indicated in ADPKD patients with large kidney and liver volumes, due to expected physical difficulties in the procedure and possible complications; [75] [79] however, no difference is seen in long-term morbidity between hemodialysis and peritoneal dialysis in ADPKD. [75]
Kidney transplantation is accepted as the preferred treatment for ADPKD patients with ESRD. [1] Among American patients on the kidney-transplant waiting list (as of December 2011), 7256 (8.4%) were listed due to cystic kidney disease and of the 16,055 renal transplants performed in 2011, 2057 (12.8%) were done for patients with cystic kidney disease, with 1,189 from deceased donors and 868 from living donors. [80]
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. [81] The CRISP study, [33] [44] mentioned in the treatment section above, contributed to build a strong rationale supporting the prognostic value of total kidney volume (TKV) in ADPKD; TKV (evaluated by MRI) increases steadily and a higher rate of kidney enlargement correlated with accelerated decline of GFR, while patient height-adjusted TKV (HtTKV) ≥600 ml/m predicts the development of stage 3 chronic kidney disease within 8 years. [81]
Besides TKV and HtTKV, the estimated glomerular filtration rate (eGFR) has also been tentatively used to predict the progression of ADPKD. [81] After the analysis of CT or MRI scans of 590 patients with ADPKD treated at the Mayo Translational Polycystic Kidney Disease Center, Irazabal and colleagues developed an imaging-based classification system to predict the rate of eGFR decline in patients with ADPKD. [81] [44] In this prognostic method, patients are divided into five subclasses of estimated kidney growth rates according to age-specific HtTKV ranges (1A, <1.5%; 1B, 1.5–3.0%; 1C, 3.0–4.5%; 1D, 4.5–6.0%; and 1E, >6.0%) as delineated in the CRISP study. [81] [44] The decline in eGFR over the years following initial TKV measurement is significantly different between all five patient subclasses, with those in subclass 1E having the most rapid decline. [81] Some of the most common causes of death in patients with ADPKD are various infections (25%), a ruptured berry aneurysm (15%), or coronary/hypertensive heart disease (40%). [82]
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.
Alport syndrome is a genetic disorder affecting around 1 in 5,000-10,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, though the changes do not usually affect vision, except when changes to the lens occur in later life. Blood in urine is universal. Proteinuria is a feature as kidney disease progresses.
A nephrectomy is the surgical removal of a kidney, performed to treat a number of kidney diseases including kidney cancer. It is also done to remove a normal healthy kidney from a living or deceased donor, which is part of a kidney transplant procedure.
Secondary hypertension is a type of hypertension which by definition is caused by an identifiable underlying primary cause. It is much less common than the other type, called essential hypertension, affecting only 5-10% of hypertensive patients. It has many different causes including endocrine diseases, kidney diseases, and tumors. It also can be a side effect of many medications.
Cystic kidney disease refers to a wide range of hereditary, developmental, and acquired conditions and with the inclusion of neoplasms with cystic changes, over 40 classifications and subtypes have been identified. Depending on the disease classification, the presentation may be at birth, or much later into adult life. Cystic disease may involve one or both kidneys and may, or may not, occur in the presence of other anomalies. A higher incidence is found in males and prevalence increases with age. Renal cysts have been reported in more than 50% of patients over the age of 50. Typically, cysts grow up to 2.88 mm annually and may cause related pain and/or hemorrhage.
Medullary cystic kidney disease (MCKD) is an autosomal dominant kidney disorder characterized by tubulointerstitial sclerosis leading to end-stage renal disease. Because the presence of cysts is neither an early nor a typical diagnostic feature of the disease, and because at least 4 different gene mutations may give rise to the condition, the name autosomal dominant tubulointerstitial kidney disease (ADTKD) has been proposed, to be appended with the underlying genetic variant for a particular individual. Importantly, if cysts are found in the medullary collecting ducts they can result in a shrunken kidney, unlike that of polycystic kidney disease. There are two known forms of medullary cystic kidney disease, mucin-1 kidney disease 1 (MKD1) and mucin-2 kidney disease/uromodulin kidney disease (MKD2). A third form of the disease occurs due to mutations in the gene encoding renin (ADTKD-REN), and has formerly been known as familial juvenile hyperuricemic nephropathy type 2.
Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca. Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.
Polycystic liver disease (PLD) usually describes the presence of multiple cysts scattered throughout normal liver tissue. PLD is commonly seen in association with autosomal-dominant polycystic kidney disease, with a prevalence of 1 in 400 to 1000, and accounts for 8–10% of all cases of end-stage renal disease. The much rarer autosomal-dominant polycystic liver disease will progress without any kidney involvement.
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease. The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure. It is a form of ciliopathy. Its incidence has been estimated to be 0.9 cases per million people in the United States, and 1 in 50,000 births in Canada.
Polycystin 1 (PC1) is a protein that in humans is encoded by the PKD1 gene. Mutations of PKD1 are associated with most cases of autosomal dominant polycystic kidney disease, a severe hereditary disorder of the kidneys characterised by the development of renal cysts and severe kidney dysfunction.
Polycystin-2(PC2) is a protein that in humans is encoded by the PKD2 gene.
Polycystic kidney disease 2-like 1 protein also known as transient receptor potential polycystic 2 is a protein that in humans is encoded by the PKD2L1 gene.
Polycystic kidney disease is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood. Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well.
Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney disease. It is associated with a group of congenital fibrocystic syndromes. Mutations in the PKHD1 cause ARPKD.
Lixivaptan (VPA-985) is an orally-active, non-peptide, selective vasopressin 2 receptor antagonist being developed as an investigational drug by Palladio Biosciences, Inc. (Palladio), a subsidiary of Centessa Pharmaceuticals plc. As of December 2021, lixivaptan is in Phase III clinical development for the treatment of Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to lixivaptan for the treatment of ADPKD.
Glomerulocystic kidney disease (GCKD) is a cystic disorder of the kidneys. GCKD involves cystic dilation of Bowman's capsule. It can occur with or without congenital abnormality.
The Polycystin Cation Channel (PCC) Family consists of several transporters ranging in size from 500 to over 4000 amino acyl residues (aas) in length and exhibiting between 5 and 18 transmembrane segments (TMSs). This family is a constituent of the Voltage-Gated Ion Channel (VIC) Superfamily. These transporters generally catalyze the export of cations. A representative list of proteins belonging to the PCC family can be found in the Transporter Classification Database.
Polycystic kidney disease 3 (autosomal dominant) is a protein that in humans is encoded by the PKD3 gene.
Thomas Martin Barratt was a British paediatrician and professor of paediatric nephrology. Barratt was most notable for developing a specialist service for children with kidney diseases in Britain, bringing peritoneal dialysis, haemodialysis, and later renal transplantation to ever younger children. Barratt was an early advocate for multidisciplinary care and developed a model that was later taken up by many other specialist centres across the world. His research led to a new treatments for many types of childhood kidney diseases., and for research into childhood Nephrotic syndrome and Hemolytic-uremic syndrome.
Shrawan Kumar, is an Indian-American geneticist, working in the fields of molecular and population genetics. He is known for his contributions in the discovery of two genes related to Branchio-oto-renal syndrome (BOR) and Autosomal Dominant Polycystic Kidney Disease (ADPKD2).
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