No abstract

Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of cyst-filled kidneys. Methods

The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available. 18: 214318: -216018: , 200718: . doi: 10.1681 Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, with an incidence of 1 in 400 to 1000 (accounting for approximately 5% of ESRD), and is characterized by the development and progressive enlargement of cysts in the kidney. ADPKD is genetically heterogeneous, with two genes identified: PKD1 (16p13.3) and PKD2 (4q21). [1][2][3][4] In linkagecharacterized populations, PKD1 accounts for approximately 85% of cases and PKD2 accounts for most of the remainder, 5,6 but further heterogeneity is possible. 7 PKD1 has an average age at ESRD of 54.3 yr, compared with 74.0 yr for PKD2. 8 PKD1 and PKD2 encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a TRP channel that may be involved in regulating intracellular Ca 2ϩ . 9,10 PC1 and PC2 interact and, similar to other cystogenic proteins, have been localized to primary cilia. 11,12 This complex may act as a flow-dependent mechanosensor that regulates the differentiated state of tubular epithelial cells. 13 The diagnosis of ADPKD is typically determined by renal imaging wit...

MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function.