Autosomal recessive polycystic kidney
|Polycystic Kidney Disease|
|Classification and external resources|
The clinical presentation of ARPKD is highly variable. Up to 50% of affected neonates die of pulmonary hypoplasia, the result of oligohydramnios 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 ensue as tubular function deteriorates. Hypertension 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, esophageal varices, and hypersplenism from periportal fibrosis.
General presenting symptoms and signs include abdominal discomfort, hematuria, urinary tract infection, incidental discovery of hypertension, abdominal mass, elevated serum creatinine, or cystic kidneys on imaging studies, patients usually have renal pain, 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 is common, and often precedes renal dysfunction. Abdominal pain 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. Hematuria may result from cyst rupture into the collecting system, or from uric acid or calcium oxalate 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, fever, and chills. Blood cultures are frequently positive, but urine culture may be negative, because infected kidney cysts do not communicate directly with the collecting duct system. 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 and extracellular matrix. Patients with ADPKD have an increased risk of cerebral hemorrhage from a ruptured intracranial aneurysm, as compared to the general population. Saccular aneurysms of the anterior cerebral circulation may be detected in up to 10% of asymptomatic patients on MRA 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 abnormalities include aortic root and annulus dilatation. Cardiac valvular abnormalities occur in 25% of patients – most commonly mitral valve prolapse and aortic regurgitation. Although most valvular lesions are asymptomatic, some may progress over time, and warrant valve replacement. Abdominal hernia and inguinal hernia also occur with a higher frequency than in the general population.
Ultrasonography reveals large, echogenic kidneys. The diagnosis can be made in utero after 24 weeks of gestation 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 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 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. Intervention should be limited to aneurysms larger than 10 mm. Someone with this disease has a 5% chance of getting brain aneurysms.
No specific therapy exists for ARPKD. Improvements in mechanical ventilation, neonatal support, blood pressure management, dialysis, and kidney transplantation have led to survival well into adulthood. Complications of hepatic fibrosis may necessitate liver transplantation. 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, especially in patients with advanced kidney dysfunction where optimizing nutritional status is important. Lipid-soluble antimicrobials, such as trimethoprim-sulfamethoxazole and quinolone antibiotics that have good tissue permeation, are the preferred therapy for infected kidney cysts. Pain-management occasionally requires cyst drainage by percutaneous aspiration, sclerotherapy with alcohol 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 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 or Everolimus).
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- Bisceglia, M; et al (2006). "Renal cystic diseases: a review". Advanced Anatomic Pathology (13): 26–56.
- Sweeney, WE; Avner ED (2006). "Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPDK)". Cell Tissue Research (326): 671–685.
- 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).
- Global Rare Diseases Patient Registry and Data Repository (GRDR) for clinical research: http://arpkd-chf.grdr.info/index.php
- The Polycystic Kidney Disease Foundation website - more details on trials, treatments, nutrition, and support.