Few diseases can cause as much distortion of an organ as autosomal dominant polycystic kidney disease (ADPKD). Many physicians have an enduring impression from the sight at surgery or at autopsy of massively enlarged polycystic kidneys or a huge cystic liver, with the parenchyma entirely replaced by cysts of variable sizes and colors ranging from pale yellow to black.
These massively enlarged organs represent the end of the spectrum of a common disease that in recent years has been diagnosed earlier and more frequently than in the past. Too often in the past, physicians approached ADPKD with undue pessimism and therapeutic nihilism, and patients trying to cope with the diagnosis were left in despair or denial. With the increased recognition of milder and earlier cases of ADPKD and advances in molecular biology, molecular genetics and medical technology, these attitudes toward ADPKD are no longer justified.
Family physicians should be able to counsel patients and their families so that this disease does not become an unreasonable burden. The article in this issue on ADPKD(1) provides useful information on the course of this disease. Five basic points for physicians will help in the management of ADPKD:
* Understand the genetic heterogeneity and marked phenotypic variability of ADPKD. The ADPKD1 gene on chromosome 16p13.3 is responsible for most cases of the disease. The ADPKD2 gene on chromosome 4 q13-q23 is responsible for a milder form of the disease. Because linkage studies were initially performed in families of patients in dialysis units, the relative prevalence of ADPKD2 has been underestimated. ADPKD2 probably accounts for at least 10 percent to 20 percent of families with ADPKD. In addition, evidence points to a third gene (ADPKD3), as well as to another gene that causes polycystic liver disease without renal involvement.
Until recently, only the ADPKD1 gene had been identified and completely sequenced. It is a very large gene and encodes a protein (polycystin), the function of which is now the focus of intensive research. The large size of the gene increases the likelihood of mutation events and may explain the high prevalence of ADPKD. The mutations so far identified are highly heterogeneous, which makes the diagnosis of the disease by direct mutation analysis difficult. For now, diagnostic genetic testing depends on linkage analysis in families with at least six relatives with an established diagnosis, of which at least two are affected.
The high phenotypic variability of ADPKD reflects the genetic heterogeneity, different mutations in the same gene, different genetic background and environmental factors. The marked effects of different genetic backgrounds and environmental factors have been clearly demonstrated in models of inherited polycystic disease in rodents.
* Distinguish ADPKD from other renal cystic diseases. The diagnosis of ADPKD in patients with a family history of the disease and a compatible phenotype is straightforward. The ultrasonographic diagnostic criteria for individuals known to be at 50 percent risk for the disease have been recently revised: two cysts, either unilateral or bilateral, for individuals less than 30 years old; two cysts in each kidney for those 30 to 59 years of age, and at least four cysts in each kidney for those over the age of 60 years. The early, but rare, clinical presentation of ADPKD in the first year of life, with large echogenic kidneys without distinct macroscopic cysts, is an exception to these criteria.
In the absence of a family history of this disease or in the presence of atypical phenotypes, other renal cystic diseases and benign simple cysts should be considered in the differential diagnosis. Renal cystic diseases that are occasionally confused with ADPKD include those associated with malformation or disruption syndromes, autosomal recessive polycystic kidney disease, tuberous sclerosis complex, von Hippel-Lindau's disease, orofaciodigital syndrome type 1, localized renal cystic disease and acquired renal cystic disease. Acquired renal cysts have been observed in conditions such as renal insufficiency, ischemia, chronic hypokalemia and renal tubular acidosis.
* Know why, when and how to screen family members for the presence of the disease. Only individuals who have been properly informed about the advantages and disadvantages of screening should be offered presymptomatic screening for ADPKD and they should receive appropriate follow-up counseling if ADPKD is diagnosed. Presymptomatic screening can be performed by ultrasound examination, which may not be conclusive before the age of 20 years, or by genetic linkage analysis, which is possible only in large families with detailed medical histories. Screening by ultrasound examination is adequate in most cases.
Prenatal diagnosis by chorionic villus sampling and DNA linkage analysis is rarely performed, since termination of pregnancy is usually not considered an acceptable option by ADPKD patients. Blood pressure monitoring and abdominal palpation to exclude large kidneys should be performed in children at risk for ADPKD, but presymptomatic screening is not in their best interest.
Young adults may benefit from presymptomatic screening. If they are not affected, they will be reassured, and if they are affected, they may benefit from specialized counseling for family planning and from the identification and management of such treatable complications as hypertension. The disadvantages of presymptomatic screening relate to insurability and employability. Recommendations will change when more effective therapies for the disease become available.
* Detect and treat conditions that may affect the outcome of ADPKD. Hypertension is a common, early and often nondiagnosed manifestation of ADPKD and may lead to early organ damage. Left ventricular hypertrophy by echocardiographic criteria develops in young adults and is an independent risk factor for premature death. Hypertension increases the morbidity and mortality caused by extrarenal manifestations of ADPKD, such as valvular heart disease, intracranial aneurysms and aortic dissections. Hypertensive cerebral hemorrhage may be more frequent than aneurysmal cerebral hemorrhage in ADPKD. The development of renal insufficiency is accompanied by severe intrarenal arterial and arteriolar sclerosis, possibly due in part to hypertension.
Existing hypertension is the most important risk factor for fetal and maternal complications during pregnancy. An early diagnosis and aggressive treatment of hypertension in ADPKD is imperative. Attention should also be paid to correction of other cardiovascular risk factors (e.g., smoking and hyperlipidemia, which have also been associated with a poor renal prognosis).
* Promptly identify problems that require specialized evaluation and treatment. Patients with flank pain, episodes of hematuria or any impairment of renal function should be evaluated by a nephrologist. Localized abdominal pain, fever and constitutional symptoms may indicate the presence of a cyst infection or, rarely, an associated malignancy. The risk of a subarachnoid hemorrhage in a patient with ADPKD is small and does not justify widespread screening for intracranial aneurysms. However, a sudden, severe and localized headache may signal aneurysmal leak. Selective presymptomatic screening for aneurysms may be warranted in subsets of patients with a higher risk.
Patients with severe polycystic liver disease should be cautioned against becoming pregnant, using oral contraceptives or taking postmenopausal estrogens. The rare patients with chronic pain due to distortion of the kidneys by large cysts and patients with severe, highly symptomatic polycystic liver disease may benefit from percutaneous cyst aspiration, alcohol sclerosis or surgical interventions. The type of treatment indicated in each case depends on the number, size and distribution of the cysts. Surgical interventions such as laparoscopic fenestration of polycystic kidneys or combined hepatic resection and cyst fenestration are difficult procedures, with significant morbidity, and should only be performed by surgeons experienced in these procedures.
Importantly, ADPKD should not be viewed as a congenital disease with a fate already determined at birth. It is an inherited disease with a highly variable and potentially modifiable clinical course. It is treatable and to some extent, its complications are preventable. The remarkable research accomplishments of the past decade have raised the hopes of physicians and patients and have planted the seeds for finding even better treatments in the near future.
(1) Beebe DK. Autosomal dominant polycystic kidney disease. Am Fam Physician 1996;53:925-35.
COPYRIGHT 1996 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group