Polycystic Kidney Disease
What is Polycystic Kidney Disease
Autosomal-dominant polycystic kidney disease is a systemic hereditary disorder transmitted in an autosomal-dominant manner. It is genetically heterogeneous; so far, two genes have been identified. The systemic manifestations include cystic and noncystic renal and extrarenal abnormalities. Renal cysts occur in 100% of gene carriers.
Autosomal-dominant polycystic kidney disease occurs throughout the world. The prevalence in reported series varies between 1 in 400 and 1 in 1,000 in people of European descent. The age- and sex-adjusted yearly incidence rate in the United States is 1.38 in 100,000. This figure almost doubles if those people in whom the diagnosis was made at autopsy are included. Overall, approximately 600,000 Americans have the disease, making Autosomal-dominant polycystic kidney disease one of the most common hereditary disorders in the United States. The frequency of the disease in people of non-European ethnic background is not known; it may be less frequent in blacks. Autosomal-dominant polycystic kidney disease is an important cause of ESRD; it accounts for approximately 4% of ESRD in the United States and 8% to 10% in Europe and Australia . In Japan, approximately 5% of patients with ESRD have Autosomal-dominant polycystic kidney disease.
Clinical Features of Autosomal-Dominant Polycystic Kidney Disease
Multiple renal cysts and progressive renal enlargement are the main clinical features present in 100% of gene carriers after 30 years of age. Extrarenal manifestations occur with variable frequency and in various combinations in both Autosomal-dominant polycystic kidney disease-1 and -2. As mentioned earlier, the polycystin proteins are expressed in virtually all tissues. Why only the renal phenotype is expressed in 100% of mutation carriers is unknown. The molecular basis for this variability could relate to the frequency with which "second hits" occur in different tissues or cells of an individual. The renal disease course is variable as well. This is in part due to genetic heterogeneity. As stated previously, the mean age at onset of ESRD is 53 to 56 years in ADPKD-1 families, but 70 to 73 years in Autosomal-dominant polycystic kidney disease-2 families. However, even in Autosomal-dominant polycystic kidney disease-1 families, marked variability of the disease course is observed. Some subjects may remain asymptomatic until old age, others enter ESRD in middle age, and a child of the same family may present with enlarged kidneys and hypertension at birth.
Diagnosis of Polycystic Kidney Disease
History, physical examination, and laboratory findings are neither sensitive nor specific for Autosomal-dominant polycystic kidney disease. Therefore, the diagnosis is usually made by renal imaging in combination with the family history, or by gene linkage analysis if at least two affected family members in addition to the proband are available for testing. However, because gene linkage analysis is cumbersome and expensive, it is used only if imaging studies are not informative and there is a need to know the diagnosis.
In clinical practice, ultrasound imaging is the primary tool for diagnosis. Ultrasound is sensitive, noninvasive, does not expose to ionizing radiation or contrast material, and is relatively inexpensive. It can be safely performed in children and pregnant women. Unlike gene linkage analysis, ultrasound imaging also gives information about the structural severity and involvement of other organs. Typical ultrasonographic findings are enlarged kidneys with multiple, often innumerable, bilateral cysts diffusely scattered throughout the parenchyma. If these findings are present in a patient with a family history of Autosomal-dominant polycystic kidney disease, the diagnosis is certain.
The diagnosis can be more difficult to establish if only a few cysts are found in normal-sized kidneys or if there is no family history. The first problem can arise when an asymptomatic, young member from an Autosomal-dominant polycystic kidney disease family wants to know whether he or she (or his or her child) is affected. Because renal cysts in Autosomal-dominant polycystic kidney disease develop and enlarge with age, young family members may have only one or a few cysts in otherwise normal-appearing kidneys. Simple renal cysts are rare in children, but relatively common in the general population, particularly over the age of 50 years. One study examined the prevalence of simple kidney cysts in the general population by performing ultrasound imaging in older subjects with normal renal function and without renal-related symptoms. Simple cysts were seen in 11.5% of subjects 50 to 70 years of age and in 22.1% of those older than 70 years. Bilateral cysts are less common in the general population, occurring in approximately 9% of people older than 70 years of age. Simple renal cysts are very rare in children; only 0.1% of children younger than 16 years of age have simple renal cysts.
Pregnancy in Polycystic Kidney Disease
The question of fertility and the influence of pregnancy on both the mother and the fetus are important issues in counseling women with polycystic kidney disease. Because of reports of ovarian cysts in women with polycystic kidney disease and immotile sperm in some men with ADPKD, the question of fertility in polycystic kidney disease is relevant. A large study of pregnancy outcomes did not find a difference in fertility between men and women with polycystic kidney disease and unaffected family members.
That study also assessed maternal and fetal complications of pregnancy, comparing 235 women with polycystic kidney disease with 108 unaffected female family members. Overall, 77% of the 605 pregnancies in the women with polycystic kidney disease resulted in a live birth, compared with 82% of 244 pregnancies in unaffected family members, which was not significantly different. The frequency of fetal complications was similar as well. However, maternal complications, mostly new or worsening hypertension, preeclampsia, and edema, were more common in the women with polycystic kidney disease than in the unaffected women (35% vs. 19%; P < 0.001). Whereas pregnancies in normotensive women were usually uncomplicated, preexisting hypertension was the most important risk factor for a maternal complication. There was no increased risk for infection: uncomplicated urinary tract infections were diagnosed in only 5 of 235 affected compared with 4 of 108 unaffected women. A renal cyst infection or acute symptoms due to nephrolithiasis occurred in three women with polycystic kidney disease. Renal function remains normal in most women with polycystic kidney disease during their childbearing years. However, having four or more pregnancies seems to exert a negative effect on renal function in women with polycystic kidney disease who are hypertensive. Rarely, women with polycystic kidney disease have decreased renal function before pregnancy. In these women, the risk for a complication and for accelerated progression to ESRD is high. This is similar to other renal diseases, in which underlying renal insufficiency carries a relatively high risk of worsening renal function during and after pregnancy.
Polycystic Kidney Disease in the Elderly
Although polycystic kidney disease can be diagnosed by imaging studies in children and often becomes symptomatic in the third and fourth decades of life, some patients remain asymptomatic until their seventh and eighth decades. Asymptomatic older subjects may be evaluated for an elevated serum creatinine or because their children are diagnosed with polycystic kidney disease. Some of these elderly subjects have unrecognized complications such as hypertension and renal insufficiency and progress to ESRD, whereas others truly have mild disease without progression to ESRD. Mild disease with late presentation is characteristic of polycystic kidney disease-2, but some polycystic kidney disease-1 families also have a mild course. In polycystic kidney disease-1 families, late presentation occurs in some parent generations, whereas their children have significantly more severe disease. Thus, an unexpected finding of multiple bilateral renal cysts in a patient aged 70 years or older with normal or only mildly decreased renal function is entirely compatible with a diagnosis of polycystic kidney disease. The oligosymptomatic nature of polycystic kidney disease in some patients is consistent with the epidemiologic data from Olmstead County, Minnesota, in which one half of all subjects with polycystic kidney disease were diagnosed only at autopsy.
Renal Replacement Therapy in Autosomal-Dominant Polycystic Kidney Disease
When patients with polycystic kidney disease reach ESRD, treatment options include hemodialysis, peritoneal dialysis, and renal transplantation. The latter is the treatment of choice if no contraindications to surgery or immunosuppressive therapy are present. Patient and graft survival with polycystic kidney disease are similar to survival in other primary renal diseases, excluding diabetic patients, who do worse. Pretransplantation native nephrectomy usually is not necessary. Exceptions are patients with a history of recurrent or recent severe renal infections, with recurrent gross hematuria, or when graft placement is difficult because of the size of the cystic kidneys. Pretransplantation evaluation should include assessment of cardiovascular status, but routine screening for colonic diverticula or intracranial aneurysms is not necessary because complications from these manifestations after transplantation are uncommon in previously asymptomatic subjects. However, one study recommends that patients with a history of diverticulitis consider colectomy before renal transplantation. Similarly, patients with a previously ruptured intracranial aneurysm or a family history of ruptured aneurysm should be screened for intracranial aneurysms (see earlier). During the first year after transplantation, patients with polycystic kidney disease may experience one complication more frequently than other patients, posttransplantation erythrocytosis. In one report, 14% of patients with polycystic kidney disease required phlebotomy compared with 4% of control subjects (P = 0.02).
Peritoneal dialysis can be offered to patients who do not have extremely large kidneys, diverticulosis, or abdominal wall hernias. Outcomes are comparable with those in patients with other underlying renal diseases, and no excess complications due to the polycystic kidneys were noted in several reports. Hemodialysis is usually well tolerated by patients with polycystic kidney disease, and they appear to have a survival advantage over patients without polycystic kidney disease on dialysis, particularly at older ages. This has been attributed to a lower prevalence of severe coronary disease in polycystic kidney disease, although cardiovascular disease remains the most common cause of death among patients with polycystic kidney disease on renal replacement therapy . Specific complications in patients on dialysis related to polycystic kidney disease include renal pain, infection, recurrent gross hematuria, and, rarely, liver cyst infection. These complications can usually be managed conservatively, but in some cases unilateral or bilateral nephrectomy may become necessary. This can now be accomplished laparoscopically, which minimizes operative risk. The kidneys decrease in size during dialysis in some but not all patients , and in some patients they further increase in size, suggesting superimposed acquired cystic disease. Renal carcinoma was rare in all studies that followed patients with polycystic kidney disease on renal replacement therapy or after transplantation.