Autosomal recessive polycystic kidney
Encyclopedia
Mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD.
It can present with Potter sequence.
Clinical Features
The clinical presentation of ARPKD is highly variable. Up to 50% of affected neonates die of pulmonary hypoplasiaPulmonary hypoplasia
Pulmonary hypoplasia is incomplete development of the lungs, resulting in an abnormally low number or size of bronchopulmonary segments or alveoli. A congenital malformation, it most often occurs secondary to other fetal abnormalities that interfere with normal development of the lungs...
, the result of oligohydramnios
Oligohydramnios
Oligohydramnios is a condition in pregnancy characterized by a deficiency of amniotic fluid. It is the opposite of polyhydramnios.-Diagnosis:Diagnosis is made by ultrasound measurement of the amniotic fluid index...
from severe intrauterine kidney disease. About 80% of those who survive the neonatal period are still alive after 10 years; however, one-third of them will have developed ESRD. Enlarged kidneys may be detected soon after birth as bilateral abdominal masses. Impaired urinary concentrating ability and metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
ensue as tubular function deteriorates. Hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
often occurs in the first few years of life. Kidney function deteriorates progressively from childhood into early adult life. Longer-term survivors frequently develop portal hypertension
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
, esophageal varices
Esophageal varices
In medicine , esophageal varices are extremely dilated sub-mucosal veins in the lower esophagus...
, and hypersplenism from periportal fibrosis.
Risk factors for progressive kidney disease include younger age at diagnosis, black race, male gender, presence of polycystin-1
PKD1
Polycystin-1 is a protein that in humans is encoded by the PKD1 gene.-Gene product:-Function:Polycystin-1 is a glycoprotein which contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail...
mutation, and hypertension.
General presenting symptoms and signs
Medical sign
A medical sign is an objective indication of some medical fact or characteristic that may be detected by a physician during a physical examination of a patient....
include abdominal discomfort, hematuria
Hematuria
In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
, urinary tract infection
Urinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
, incidental discovery of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, abdominal mass
Abdominal mass
An abdominal mass is any localized enlargement or swelling in the human abdomen. Depending on its location, the abdominal mass may be caused by an enlarged liver , enlarged spleen , protruding kidney, a pancreatic mass, a retroperitoneal mass , an abdominal aortic aneurysm, or various tumours, such...
, elevated serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
, or cystic kidneys on imaging studies, patients usually have renal pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, and develop renal insufficiency.
ARPKD-Specific:
The classic presentation for ARPKD is systemic hypertension with progression to end-stage renal disease (ESRD) by the age of 15. In atypical presentation, a small number of ARPKD sufferers live to adulthood with some kidney function; but with significant deterioration in liver function. This outcome is postulated to result from expression of the polycystic kidney and hepatic disease gene PKHD1, which is located on chromosome 6p.
ADPKD-Specific:
ADPKD is associated with pathologies in other body systems, in contrast to ARPKD. In 50% of the cases cysts appear in other abdominal organs in including the liver, pancreas, spleen, lung, seminal vesicles, and ovaries. 10 to 30% have Berry aneurysms in the Circle of Willis cerebral circulation. The most common sites for cysts include the coronary arteries; and abnormalities in cardiac valves, hernias, and diverticuli are all documented.
Clinical Course:
Approximately 50% of patients with ADPKD have end-stage renal disease (ESRD) by the age of 60, but those with ADPKD-2 tend to have later onset and slower progression. Hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
is common, and often precedes renal dysfunction. Abdominal pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
and early satiety and gastroesophageal reflux symptoms are common, due to the mass effect of the enlarged kidneys. Cyst rupture or hemorrhage into a cyst may produce acute pain or symptoms and signs of localized peritonitis
Peritonitis
Peritonitis is an inflammation of the peritoneum, the serous membrane that lines part of the abdominal cavity and viscera. Peritonitis may be localised or generalised, and may result from infection or from a non-infectious process.-Abdominal pain and tenderness:The main manifestations of...
. Hematuria
Hematuria
In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
may result from cyst rupture into the collecting system, or from uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
or calcium oxalate
Calcium oxalate
Calcium oxalate is a chemical compound that forms needle-shaped crystals, known in plants as raphides. A major constituent of human kidney stones, the chemical is also found in beerstone, a scale that forms on containers used in breweries...
kidney stones. Nephrolithiasis occurs in about 20% of patients.
Urinary tract infection occurs with increased frequency in ADPKD. Infection in a kidney or liver cyst is a particularly serious complication. It is most often due to Gram-negative bacteria, and presents with pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, and chills. Blood culture
Blood culture
Blood culture is a microbiological culture of blood. It is employed to detect infections that are spreading through the bloodstream...
s are frequently positive, but urine culture may be negative, because infected kidney cysts do not communicate directly with the collecting duct system
Collecting duct system
The collecting duct system of the kidney consists of a series of tubules and ducts that connect the nephrons to the ureter. It participates in electrolyte and fluid balance through reabsorption and excretion, processes regulated by the hormones aldosterone and antidiuretic hormone.There are several...
. Distinguishing between infection and cyst hemorrhage is often a challenge, and the diagnosis relies mainly on clinical and bacteriological findings. Radiological and nuclear imaging studies are generally not helpful.
Numerous extrarenal manifestations of ADPKD highlight the systemic nature of the disease, and likely reflect a generalized abnormality in collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
and extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
. Patients with ADPKD have an increased risk of cerebral hemorrhage from a ruptured intracranial aneurysm
Aneurysm
An aneurysm or aneurism is a localized, blood-filled balloon-like bulge in the wall of a blood vessel. Aneurysms can commonly occur in arteries at the base of the brain and an aortic aneurysm occurs in the main artery carrying blood from the left ventricle of the heart...
, as compared to the general population. Saccular aneurysms of the anterior cerebral circulation
Cerebral circulation
Cerebral circulation refers to the movement of blood through the network of blood vessels supplying the brain. The arteries deliver oxygenated blood, glucose and other nutrients to the brain and the veins carry deoxygenated blood back to the heart, removing carbon dioxide, lactic acid, and other...
may be detected in up to 10% of asymptomatic patients on MRA
Magnetic Resonance Angiography
Magnetic resonance angiography is a group of techniques based on Magnetic Resonance Imaging to image blood vessels. Magnetic resonance angiography is used to generate images of the arteries in order to evaluate them for stenosis , occlusion or aneurysms...
screening, but most are small, have a low risk of spontaneous rupture, and do not merit the risk of intervention. In general, hemorrhage tends to occur before the age of 50 years. In patients with a family history of intracranial hemorrhage, those who have survived a previous bleed have aneurysms larger than 10 mm, and have uncontrolled hypertension. Other vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....
abnormalities include aortic root and annulus dilatation. Cardiac valvular abnormalities occur in 25% of patients – most commonly mitral valve prolapse
Mitral valve prolapse
Mitral valve prolapse is a valvular heart disease characterized by the displacement of an abnormally thickened mitral valve leaflet into the left atrium during systole. There are various types of MVP, broadly classified as classic and nonclassic. In its nonclassic form, MVP carries a low risk of...
and aortic regurgitation. Although most valvular lesions are asymptomatic, some may progress over time, and warrant valve replacement
Valve replacement
Valve replacement surgery is the replacement of one or more of the heart valves with either an artificial heart valve or a bioprosthesis . It is an alternative to valve repair.There are four procedures:...
. Abdominal hernia
Hernia
A hernia is the protrusion of an organ or the fascia of an organ through the wall of the cavity that normally contains it. A hiatal hernia occurs when the stomach protrudes into the mediastinum through the esophageal opening in the diaphragm....
and inguinal hernia
Inguinal hernia
An inguinal hernia is a protrusion of abdominal-cavity contents through the inguinal canal. They are very common , and their repair is one of the most frequently performed surgical operations....
also occur with a higher frequency than in the general population.
Diagnosis
Ultrasonography reveals large, echogenic kidneys. The diagnosis can be made in uteroIn utero
In utero is a Latin term literally meaning "in the womb". In biology, the phrase describes the state of an embryo or fetus. In legal contexts, the phrase is used to refer to unborn children. Under common law, unborn children are still considered to exist for property transfer purposes.-See also:*...
after 24 weeks of gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
in severe cases, but cysts generally become visible only after birth. The absence of renal cysts in either parent on ultrasonography helps to distinguish ARPKD from ADPKD in older patients. The wide range of different mutations and the large size of the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
complicate molecular diagnosis, although prenatal diagnosis is possible by gene linkage to the PKHD1 locus in families with a previous confirmed ARPKD birth.
The sensitivity of renal ultrasonography for the detection of ADPKD is 100% for subjects 30 years or older with a positive family history. Diagnostic criteria require two or more cysts in one kidney and at least one cyst in the contralateral kidney in young subjects, but four or more in subjects older than 60 years, because of the increased frequency of benign simple cysts. Most often, the diagnosis is made from a positive family history
Family history
Family history is the systematic narrative and research of past events relating to a specific family, or specific families.- Introduction :...
and imaging studies showing large kidneys with multiple bilateral cysts and possibly liver cysts. Before the age of 30 years, CT scan or T2-weighted MRI is more sensitive for detecting presymptomatic disease because the sensitivity of ultrasound falls to 95% for ADPKD type 1 and <70% for ADPKD type 2. Genetic counseling is essential for those being screened. It is recommended that screening for asymptomatic intracranial aneurysms should be restricted to patients with a personal or family history of intracranial hemorrhage
Intracranial hemorrhage
An intracranial hemorrhage is a hemorrhage, or bleeding, within the skull.-Causes:Intracranial bleeding occurs when a blood vessel within the skull is ruptured or leaks. It can result from physical trauma or nontraumatic causes such as a ruptured aneurysm...
. Intervention should be limited to aneurysms larger than 10 mm. Someone with this disease has a 5% chance of getting brain aneurysms.
Treatment
No specific therapy exists for ARPKD. Improvements in mechanical ventilationMechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
, neonatal support, blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
management, dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
, and kidney transplantation
Kidney transplantation
Kidney transplantation or renal transplantation is the organ transplant of a kidney into a patient with end-stage renal disease. Kidney transplantation is typically classified as deceased-donor or living-donor transplantation depending on the source of the donor organ...
have led to survival well into adulthood. Complications of hepatic fibrosis may necessitate liver transplantation
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
. Future therapies may target aberrant cell signaling mechanisms, as in ADPKD.
At present, treatment is largely supportive, as there is no single therapy that has been shown to prevent the decline in kidney function. Hypertension control with a target blood pressure of 130/85 or less is recommended. Lower levels have been reported to slow the rate of loss of kidney function. A multidrug approach that includes agents to inhibit the renin-angiotensin system is frequently required. There is no compelling evidence to recommend a low-protein diet
Low-protein diet
A low-protein diet is a diet in which people reduce their intake of protein. A low-protein diet is often prescribed to people with kidney or liver disease...
, especially in patients with advanced kidney dysfunction where optimizing nutritional status is important. Lipid-soluble antimicrobials, such as trimethoprim-sulfamethoxazole and quinolone
Quinolone
The quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone refers to potent synthetic chemotherapeutic antibacterials....
antibiotics that have good tissue permeation, are the preferred therapy for infected kidney cysts. Pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
-management occasionally requires cyst drainage by percutaneous aspiration, sclerotherapy
Sclerotherapy
Sclerotherapy is a procedure used to treat blood vessels or blood vessel malformations and also those of the lymphatic system. A medicine is injected into the vessels, which makes them shrink. It is used for children and young adults with vascular or lymphatic malformations...
with alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
or, rarely, surgical drainage. Patients with ADPKD appear to have a survival advantage on either peritoneal or hemodialysis compared to patients with other causes of ESRD. Those undergoing kidney transplantation may require bilateral nephrectomy
Nephrectomy
Nephrectomy is the surgical removal of a kidney.-History:The first successful nephrectomy was performed by the German surgeon Gustav Simon on August 2, 1869 in Heidelberg. Simon practiced the operation beforehand in animal experiments...
if the kidneys are massively enlarged or have been the site of infected cysts. Post-transplantation survival rates are similar to those of patients with other causes of kidney failure, but patients remain at risk for the extrarenal complications of ADPKD.
Studies in animal models of inherited cystic disease have identified promising therapeutic strategies, which are undergoing clinical research, including vasopressin V2 receptor antagonists (such as Tolvaptan), and mTOR inhibitors (such as Sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
or Everolimus
Everolimus
Everolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
).
External links
- GeneReviews/NIH/NCBI/UW entry on Polycystic Kidney Disease, Autosomal Recessive
- ARPKD/CHF Alliance at http://www.arpkdchf.org, for information on ARPKD and Congenital Hepatic Fibrosis (CHF).
- The Polycystic Kidney Disease Foundation website - more details on trials, treatments, nutrition, and support.