Variation in age at ESRD in autosomal dominant polycystic kidney disease.

BACKGROUND: Heterogeneity manifest as more severe disease in successive generations has been attributed to genetic anticipation in patients with autosomal dominant polycystic kidney disease (ADPKD). We evaluated variation in age at end-stage renal disease (ESRD) in ADPKD families for evidence of anticipation. STUDY DESIGN: Retrospective. SETTING & PARTICIPANTS: 413 families with ADPKD seen at our single center between 1985 and 2004 (including 95 families with documented polycystic disease type 1 [PKD1] and 213 ADPKD families with parents born before 1930). PREDICTOR: Generational status. OUTCOME: Age at ESRD onset. MEASUREMENTS: Time to ESRD was evaluated by using survival analysis, Cox regression, and descriptive statistics. Unstable trinucleotide repeat expansion was evaluated by means of genotyping in 6 PKD1 families. RESULTS: We analyzed 413 ADPKD families (1,391 parent-offspring pairs) with known age at ESRD or last known age without ESRD (informative pairs). There was no difference in age at ESRD between parents and offspring by means of Cox regression after adjusting for correlations among family members and sex (hazard ratio, 1.019; 95% confidence interval, 0.919 to 1.13; P = 0.7). Similar analysis of PKD1 informative pairs and those with parents born before 1930 showed no differences in age at ESRD. Male ADPKD patients were 42% more likely to reach ESRD (P < 0.001), and male patients with documented PKD1 were 41% more likely to reach ESRD (P = 0.01) than female patients. LIMITATIONS: Hypertension treatment unknown. CONCLUSIONS: We found no evidence for anticipation of ESRD in patients with ADPKD; thus, the observed variation in age at ESRD may result from other genetic, sex, or environmental causes.

Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) often develop hypertension before any abnormalities in renal function are detected clinically. Therefore, standard screening (serum creatinine and urinalysis) of young individuals with unexplained hypertension to exclude renal parenchymal disease would rarely detect ADPKD. METHODS: Data from 516 subjects with ADPKD (217 male and 299 female), aged newbornto 55 years with a normal serum creatinine and no proteinuria based on urine dipstick, studied between 1985 and 2000, were compared with data from similar subjects from the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and NHANES IV (1999-2000) data, by gender. RESULTS: There was a highly significant occurrence of hypertension in young patients with ADPKD when compared to patients aged 20 to 34 years in the U.S. population. The hypertension in patients with ADPKD occurred in the absence of abnormal renal function or abnormal urinalysis. CONCLUSIONS: These data indicate that renal ultrasound screening of young hypertensive individuals (aged 20 to 34 years) should be considered when searching for causes of secondary hypertension. Identifying affected ADPKD individuals early in their disease will permit aggressive blood pressure treatment and early inhibition of the renin-angiotensin-aldosterone system, which has been shown to reverse left ventricular hypertrophy, an important cardiovascular risk factor. In the present era of renal replacement therapy, cardiovascular complications are the main cause of death in patients with ADPKD.

Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome.

Normal reabsorption of glomerular filtrate proteins probably requires recycling of the endocytic receptors megalin (gp330) and cubilin. Both receptors are located on the luminal surface of the renal proximal tubule epithelium. Whether abnormal amounts of receptor are present in the urine of patients with Dent's disease, Lowe's syndrome, or autosomal dominant idiopathic Fanconi syndrome was explored. They are all forms of the renal Fanconi syndrome and are associated with tubular proteinuria. Urine samples of equal creatinine contents were dialyzed, lyophilized, and subjected to electrophoresis on nonreducing sodium dodecyl sulfate-5% polyacrylamide gels. Proteins were blotted and probed with anti-megalin IgG, anti-cubilin IgG, or receptor-associated protein. Megalin and cubilin levels detected by immunochemiluminescence were measured as integrated pixels and expressed as percentages of the normal mean values. A striking deficiency of urinary megalin, compared with normal individuals (n = 42), was observed for eight of nine families with Dent's disease (n = 10) and for the two families with Lowe's syndrome (n = 3). The family with autosomal dominant idiopathic Fanconi syndrome (n = 2) exhibited megalin levels within the normal range. The measured levels of cubilin were normal for all patients. These results are consistent with defective recycling of megalin to the apical cell surface of the proximal tubules and thus decreased loss into urine in Dent's disease and Lowe's syndrome. This defect would interfere with the normal endocytic function of megalin, result in losses of potential ligands into the urine, and produce tubular proteinuria.