Survival after end-stage renal disease in autosomal dominant polycystic kidney disease: contribution of extrarenal complications to mortality.

Autosomal dominant polycystic kidney disease (ADPKD) accounts for 8% to 10% of patients with end-stage renal disease (ESRD) in the United States and Europe. Progressive expansion of multiple bilateral renal cysts leads to massive enlargement of the kidneys and progressive renal failure. Extrarenal manifestations of ADPKD, such as liver cysts, intracranial aneurysms, cardiac valvular disease, and perhaps diverticulosis, have been documented extensively in cross-sectional studies, but little is known about their natural history. It is thought that extrarenal aspects of ADPKD contribute to increased mortality, yet survival on dialysis of the ADPKD population surpasses that of the general dialysis population. To address this issue, we analyzed the relative risk and causes of death after ESRD in ADPKD versus nondiabetic controls using data from the United States Renal Data System. Relative risk of death from any cause, including the major extrarenal manifestations of ADPKD, was determined as a function of ESRD treatment modality (dialysis or transplantation). We found a lower total mortality rate in ADPKD ESRD patients compared with nondiabetic control ESRD patients (relative risk of death in ADPKD = 0.57; P < 0.001). Mortality rates of extrarenal complications except for polycystic liver disease were similar or lower in ADPKD patients than in nondiabetic controls. Mortality secondary to extrarenal complications was substantially lower than that secondary to cardiovascular or cerebrovascular disease.

Using survival methods to estimate age-at-onset distributions for genetic diseases with an application to Huntington disease.

Two important considerations in genetic disease are the risk of inheriting the gene for a disease and the age-at-onset distribution among those inheriting it. This paper describes the use of survival data analytic methods to estimate these entities. When a sample consists of children and/or siblings of affected individuals, standard life-table methods such as Kaplan-Meier techniques can be applied. The desired estimators are functions of the Kaplan-Meier estimator and their properties are derived using the invariance principle and delta methods. A discussion of the underlying assumptions and estimators of standard errors and mean onset age are given. In an application to Huntington disease, the risk (+/- SE) of inheriting the gene for disease among children of a singly affected parent is estimated to be 0.499 +/- 0.020 and the estimated mean onset age (+/- SE) is 45.6 +/- 0.7.

Maternal factors in onset of Huntington disease.

Analyses of father-offspring and mother-offspring similarity in onset age suggest that nuclear genes account for a significant portion of the modification of onset age in Huntington disease. The effects of non-nuclear modifiers are supported by the finding that the offspring of affected women have significantly older mean ages of onset than offspring of affected men irrespective of the onset age in the parent. The absence of increased father-daughter similarity indicates that modification is not X-linked. The absence of reproductive advantage for late-onset individuals and the absence of a multigenerational maternal-lineage effect suggest that the modifying effect of the sex of the affected parent occurs in a single parental generation. Offspring of affected women with onset between ages 35 and 49 had a significantly older mean onset age than their mothers. This suggests that a protective effect may be conferred upon the offspring of affected women.