Diagnosis Of Autosomal Dominant Polycystic Kidney Disease Research Articles

Characterization of microsatellite markers adjacent to AP-4 on chromosome 16p13.3

The 1400 kb genomic sequence between the markers D16S406 and D16S423 on chromosome 16p13.3 has been recently sequenced and the interval contains a transcription factor, AP-4, that was identified as a ligand for immunoglobulin-kappa promoter E-box elements,1suggesting that AP-4 may be related to immunodeficiency diseases. In addition, chromosome 16p13.3 includes a number of genes including the PKD1 gene,2,3the autosomal dominant polycystic kidney disease (ADPKD) gene. ADPKD is characterized by progressive development and enlargement of renal cysts.4The size and genomic complexity of the PKD1 gene makes it impractical to detect mutations for prenatal diagnosis. Therefore, pedigree-based linkage analysis remains useful for diagnosis of ADPKD. To increase the number of polymorphic markers in the region aroundAP-4 gene, we performed database searches of 1400 kb of genomic sequence (from contig NT000677 to NT001573: http://www.ncbi.gov/genome/seq.cgi) across the 16p13.3. A number of dinucleotide or tetranucleotide repeats were found, and 20 microsatellites that contain more than 15 contiguous repeats were chosen for further investigation.

The vasculopathy of autosomal dominant polycystic kidney disease: Insights from animal models

A 37-year-old white man with autosomal dominant polycystic kidney disease (ADPKD) was admitted to Boston's Beth Israel Hospital with sudden severe headache of two-hour duration. He was unconscious on admission. Emergency angiography revealed a ruptured 15 mm cerebral aneurysm. Emergency surgery to clip the aneurysm was unsuccessful, and the patient died 36 hours after admission. His serum creatinine was 3.2 mg/dL on admission; the rest of his laboratory values were within normal limits. A request for an autopsy was denied. At age 20, the patient and his then 15-year-old sister had abdominal ultrasound examinations that revealed bilateral renal cysts, consistent with the diagnosis of ADPKD. At age 32, the patient had a sudden, relatively severe, acute myocardial infarction (MI). Cardiac catheterization revealed three-vessel disease, and he subsequently underwent a triple coronary artery bypass operation. Throughout his medical course, the patient's blood pressure was in the 120/80 to 140/80 mm Hg range while he was taking lisinopril, 10 mg/day, which was started after his MI. The patient's mother has ADPKD and end-stage renal disease, and she is on hemodialysis. She recently underwent unsuccessful renal transplantation. There is no known family history of cerebral aneurysms. However, the mother had two cerebrovascular accidents and recovered from both. The patient's father had an MI at age 32, but he lived to age 64. A paternal uncle also died at an early age of an MI. The patient's younger sister was later screened for cerebral aneurysms and the test was negative. The patient's two young children have not been screened for ADPKD.

Presymptomatic molecular diagnosis of autosomal dominant polycystic kidney disease using PKD1‐and PKD2‐linked markers in Cypriot families

Autosomal dominant polycystic kidney disease (ADPKD), is a heterogeneous disorder, primarily characterized by the formation of cysts in the kidneys, and the late development in life of progressive chronic kidney failure. Three genes are implicated in causing ADPKD. One on chromosome 16, PKD1, accounts for 85-90% of all cases, and the PKD2 gene on chromosome 4 accounts for the remainder. A very rare third locus is still of unknown location. We used PKD1- and PKD2-linked polymorphic markers to make the diagnosis of ADPKD in young presymptomatic members in affected families. We showed that in young members of families where clinical diagnosis cannot be definitively established, molecular linkage analysis can assist clinicians in the diagnosis. In one family a 24-year old had one cyst on the right kidney; however, molecular analysis showed clearly that he had inherited the normal haplotype. In another family, in one part of the pedigree there was co-inheritance of the disease with a PKD1-linked haplotype which originated in a non-affected 78-year-old father. Analysis with PKD2-linked markers excluded this locus. The data can be explained in one of two ways. Either this family phenotype is linked to a third locus, or the proband was the first affected person, most probably because of a novel mutation in one of her father's chromosomes. In conclusion, the combined use of markers around the PKD1 and the PKD2 locus provides more definitive answers in cases where presymptomatic diagnosis is requested by concerned families.

A century of mortality in five large families with polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) characteristically leads to end-stage renal failure in the fifth or sixth decade of life, which in the absence of therapeutic measures will lead to premature death. To determine excess mortality relative to the general population and chromosome 16-linked ADPKD patients, we studied 348 individuals who belonged to five large ADPKD families and who had at least a 50% probability of carrying the gene; the study data derive from a time span of approximately one century. Assessment of the diagnosis of ADPKD in the present generation was based on the characteristic roentgenographic appearance of polycystic kidneys and was confirmed by DNA analysis with flanking polymorphic markers around the polycystic gene. In the previous generation, we used Mendelian reasoning after pedigree analysis to identify persons with a 50% or 100% probability of carrying the polycystic gene. During the study period (1889 to 1992), 83 deaths occurred in 10,279 person-years. Mortality was increased 1.6-fold (95% confidence interval, 1.3 to 2.0) relative to the general population and was independent of the gender of the affected family member as well as the gender of the transmitting parent. The increased mortality was strongest in the 50 to 59 year age group (relative mortality, 3.2; 95% confidence interval, 2.0 to 4.8), but decreased after the 1970s, probably as a result of improvements in supportive care and, eventually, renal replacement therapy. In conclusion, the total life-span in ADPKD patients is improving, but remains low in comparison to the general population, and the gender of the transmitting parent or of the affected individual does not influence relative mortality.

Drooping upper eyelids and polycystic kidney disease.

Over the last 26 yr, 33 cases and/or families of patients with autosomal dominant polycystic kidney disease (ADPKD) and a particular appearance of the eyes have been observed. ADPKD was unremarkable and in most cases had led to the usual slow development of end-stage renal failure. The facial feature concerned the upper eyelid, which drooped obliquely over the eyeball with a fold hiding the upper segment of the iris (blepharochalasis). The aspect was so typical that the diagnosis of ADPKD was suggested on first contact with new renal patients. All affected patients were white, of various origins, including French, Polish, Scandinavian, Italian, and Spanish. In retrospect, drooping eyelids had been present in the parents and/or grandparents who had died of renal failure, with or without an established diagnosis of ADPKD. In order to disclose the cosegregation of blepharochalasis with ADPKD, the screening of its prevalence in a well-circumscribed region with a catchment population of 410,000 was undertaken. The facial feature was found in 24 (32%) of 75 ADPKD families. Family transmission was confirmed in those kindreds, because at least two members suffered from ADPKD. Cosegregation was sought by analyzing family group photographs taken over several generations, the oldest member of which was born in 1973. All members with blepharochalasis had died of renal failure or are presently being followed up for ADPKD. A bibliographic search showed that the association of ocular and/or eyelid deformities and various inborn renal diseases is far from rare, suggesting a simultaneous event in the embryonic timetable.(ABSTRACT TRUNCATED AT 250 WORDS)

The spectrum of autosomal dominant polycystic kidney disease in children.

The natural history of autosomal dominant polycystic kidney disease (ADPKD) has not been well described in children, and it is not known whether a relationship exists between renal structural abnormalities and function in children as has been seen in adults. Therefore, 140 children from 67 ADPKD families were studied in a prospective study. Only 22 children came with a previous diagnosis of ADPKD. In 44% of all children, at least one cyst was found on ultrasound at a mean age of 8.7 yr. Of these, 60% were classified as having moderate disease on the basis of a total cyst number of 1 to 10 cysts, whereas 40% were considered to have severe disease with a total of more than 10 cysts. There was a significant relationship between the severity of the renal structural involvement and the frequency of flank and back pain, hypertension, and impaired renal concentrating capacity. However, GFR were not reduced in children with ADPKD and did not relate to structural severity. Thirty-nine children were seen for a follow-up visit 2 to 5 yr after the initial visit. No child had progressed from nonaffected to affected with ADPKD, but three of four children with only one cyst at the time of the initial study had progressed to bilateral cysts. Among the 22 ADPKD children who had a follow-up study, there was progression of the disease, reflected by an increase in cyst number and an increase in the frequency of pain and hypertension. However, GFR remained stable in all children.(ABSTRACT TRUNCATED AT 250 WORDS)

Study of prognostic factors for renal function in patients with autosomal dominant polycystic kidney disease

To examine clinical features and the prognostic factors for renal function in patients with autosomal dominant polycystic kidney disease (ADPKD), a total of 118 patients (60 men and 58 women) were followed for 3 to 192 months (mean 77 months). The mean age of men at the diagnosis of ADPKD was younger than that of women. Main Symptoms were hematuria, hypertension and proteinuria. Forty-one % of the patients showed deterioration of renal function at the diagnosis. The rate of residual volume of renal parenchyma on CT findings was correlated well with renal function. Twenty-eight % of the patients preserved good and stable renal functions for over 5 years, while most of others had deterioration in their renal function. Thirty-four % of the patients started dialysis within 79 +/- 62 months from the diagnosis. The frequency of end stage renal failure was 7% at 40 years, 21% at 50 years, 36% at 60 years and 63% at 70 years old, respectively. Men needed hemodialysis at younger ages than women. Renal function of the patients with hypertension was worse than that of the patients without hypertension. The ratio of the value of P.S.P.120 to that of serum creatinine (PSP120/sCr), and the rate of residual volume of renal parenchyma revealed distinct prognostic factors for renal function.

Saccular intracranial aneurysms in autosomal dominant polycystic kidney disease.

The literature on the association of intracranial aneurysms in autosomal dominant polycystic kidney disease (ADPKD) consists mainly of case reports and small series of patients. To provide a more-detailed description of this association and its frequency, the records of all ADPKD patients with saccular intracranial aneurysms, all ADPKD autopsy cases including brain examination, and sex- and age-matched autopsy cases without ADPKD seen at the Mayo Clinic between 1950 and 1989 and of all Rochester residents with a diagnosis of subarachnoid hemorrhage or ADPKD between 1945 and 1984 were reviewed. The presentation of the 41 patients (22 men and 19 women; mean age, 46.4 yr) with this association was subarachnoid hemorrhage in 33, transient ischemic attacks in 2, incidental angiographic or autopsy finding in 5, and discovery during angiographic screening in 1. Thirty-one, seven, and three patients harbored one, two, and three aneurysms, respectively, arising from the middle cerebral artery (N = 23), anterior communicating artery (N = 16), internal carotid artery (N = 11), and vertebral or basilar artery (N = 4). A family history of intracranial aneurysm, subarachnoid hemorrhage, or intracranial hemorrhage at an early age was present in 22% of the patients. Small aneurysms (less than 5 mm) were less likely to have ruptured or caused symptoms (P less than 0.04). There was a trend for hypertension to be associated with the severity of the subarachnoid hemorrhage. Aneurysmal rupture occurred before age 50 in 64% of patients. Of the 89 ADPKD autopsy cases with brain examination, 22.5% had intracranial aneurysms.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Manifestations of Autosomal Dominant Polycystic Kidney Disease in Patients Older Than 50 Years

The purpose of this study was to define manifestations of autosomal dominant polycystic kidney disease (ADPKD) in older patients with the disease. Fifty-seven subjects age 50 years or more, who were at risk for having inherited the gene for ADPKD, were evaluated for renal size, hypertension, back and abdominal pain, symptoms consistent with urinary tract infection (UTI), hematuria, end-stage renal failure, and liver cysts. The diagnosis of ADPKD was made in 32 of the 57 at-risk subjects (56%). At the time of study, only one patient with the disease was asymptomatic and normotensive and denied any previous symptoms suggestive of the disease. Clinical manifestations of ADPKD in the 31 symptomatic patients were hypertension (69%), a history of back and abdominal pain (47%), symptoms consistent with UTI (41%), hematuria (31%), and end-stage renal failure (47%). Liver cysts were found in 44% of patients. No statistically significant differences in the frequency of any manifestations of ADPKD between men and women were found, although the frequency of symptoms consistent with UTI tended to be higher in women (53%) than in men (27%). Most patients developed symptoms after the age of 40 years. Notably, 31% of the older patients with ADPKD had normal serum creatinine levels. Thus, older subjects with kidney cysts who are at risk to have inherited the gene for ADPKD, should be considered to have the disease even in the presence of well-preserved kidney function. This observation may play an important role in assessing the prognosis of older subjects at risk who have bilateral renal cysts and in genetic counseling of their relatives.

The staphylococcus and the newborn child.

<h3>Context</h3> Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder that can cause hypertension during childhood, but the true prevalence of hypertension during childhood is not known. <h3>Objective</h3> We undertook a systematic review and meta-analysis to determine the prevalence of hypertension in children with ADPKD. <h3>Data sources</h3> Systematic review of articles published between 1980 and 2015 in MEDLINE and EMBASE. <h3>Study selection</h3> Studies selected by two authors independently if reporting data on prevalence of hypertension in children and young persons aged &lt;21 years with a diagnosis of ADPKD. Observational series were included with study populations of &gt;15 children. Articles were excluded if inadequate diagnostic criteria for hypertension were used. Studies with selection bias were included but analysed separately. <h3>Data extraction</h3> Data extracted on prevalence of hypertension, proteinuria and reduced renal function using standardised form. Meta-analysis was performed to calculate weighted mean prevalence. <h3>Results</h3> 903 articles were retrieved from our search; 14 studies met the inclusion criteria: 1 prospective randomised controlled trial; 8 prospective observational studies; and 5 retrospective cross-sectional studies. From 928 children with clinically confirmed ADPKD, 20% (95% CI 15% to 27%) were hypertensive. The estimated prevalence of proteinuria in children with ADPKD is 20% (8 studies; 95% CI 9% to 40%) while reduced renal function occurred in 8% (5 studies; 95% CI 2% to 26%). <h3>Limitations</h3> Studies showed a high degree of methodological heterogeneity (I²=73.4%, τ²=0.3408, p&lt;0.0001). Most studies did not use ambulatory blood pressure (BP) monitoring to diagnose hypertension. <h3>Conclusions</h3> In this meta-analysis we estimate 20% of children with ADPKD have hypertension. In the population, many children with ADPKD are not under regular follow-up and remain undiagnosed. We recommend that all children at risk of ADPKD have regular BP measurement.