Autosomal dominant polycystic kidney disease

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Autosomal dominant polycystic kidney disease
Other namesAutosomal dominant PKD, adult-onset PKD
Polycystic kidneys
SpecialtyMedical genetics Edit this on Wikidata

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening

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]

Signs and symptoms

Among the clinical presentation are:[citation needed]

Signs and symptoms of ADPKD often develop between 30 and 40 years of age.[11]

Genetics

ADPKD is genetically heterogeneous with two

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]

Pathophysiology

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

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.

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]

Illustration of PKD1 and PKD2 proteins at the cell membrane

Diagnosis

Usually, the diagnosis of ADPKD is initially performed by renal imaging using

genetic diagnosis.[34][36]

The findings of large

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

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
]

  • Adult polycystic kidney
    Adult polycystic kidney
  • Diagram of autosomal dominant polycystic disease with a normal kidney inset for comparison
    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)
    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).[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.

Aquaretic medication

In 2014, Japan was the first country in the world to approve a pharmacological treatment for ADPKD

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]

Dietary and lifestyle interventions

Research using ADPKD mouse models showed that mild food restriction strongly improved disease progression.

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]

Analgesic medication

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]

Renal cyst aspiration

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

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]

Neurolysis

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]

Nephrectomy

Many ADPKD patients experience symptomatic sequelae in consequence of the disease, such as cyst

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]

Dialysis

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 transplant

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]

Prognosis

In ADPKD patients, gradual cyst development and expansion result in kidney enlargement, and during the course of the disease,

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]

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