Preeclampsia and risk for subsequent ESRD in populations of European ancestry.

Several recent studies reveal the link between preeclampsia and future development of ESRD, CKD, and microalbuminuria (1–3). Preeclampsia is also associatedwith the subsequent development of cardiovascular disease (CVD) (4–6). Whether the pathogenesis of preeclampsia represents an unmasking of subclinical or unrecognized kidney disease, an independent insult to the kidneys leading to progressive CKD, or a sign of underlying systemic endothelial dysfunction destined to progress to end-organ vascular disease with heightened risk for subsequent CVD and CKD remains unknown. In an attempt to answer this important clinical question, Vikse et al. evaluated associations between the long-term risk for ESRD by linking comprehensive registries that contained birth and subsequent health records in large numbers of Norwegians (7). Index cases were selected on the basis of their personal history of preeclampsia, along with the presence or absence of preeclampsia in their siblings and children and the families of their spouses. The subsequent rates of ESRD were computed in thosewith sporadic preeclampsia, as well as those with differing family histories of preeclampsia (7). Traditional risk factors for preeclampsia are known to include a paternal or maternal history of this pregnancy-associated disorder (8–11). In addition, ESRD clusters in the families of index cases of European and European American ethnicity (12–14). Therefore, it was reasonable for the authors to postulate that if the rate of subsequent ESRD was higher among preeclamptic women who had siblings or offspring also affected by preeclampsia, then a heritable or genetically mediated systemic disorder (perhaps susceptibility to generalized vascular endothelial dysfunction) might be present in families. This process could ultimately lead to both renal and CVD complications. However, their exhaustive evaluation using large and unique databases suggests this is not the case. The authors performed a retrospective analysis involving four Norwegian cohorts. They examined the siblings and children of 510,598 men and 570,675 women who had a registered birth during a 41-year study period. The long term risk for development of ESRD was compared in women without preeclampsia and without a sibling who had preeclampsia, relative to the following: (1) women without preeclampsia but with a sibling who had preeclampsia, (2) women with preeclampsia who lacked siblings with preeclampsia, and (3) women with preeclampsia who had a sibling with preeclampsia. The authors collected and analyzed maternal, paternal, sibling, and partner relationships. Results were ultimately truncated for those who were entered in the registry in later years, when no further cases of ESRD were ascertained. Compared with women without preeclampsia and without an affected sibling, women experiencing preeclampsia without a similarly affected sibling had a profound and statistically significant six-fold increase in their long-term risk for ESRD. When the sibling of a preeclamptic woman also had preeclampsia, the risk for ESRD in the index case was somewhat attenuated (relative risk, 2.8). However, when only a sibling had preeclampsia (not the woman in question), no increase in risk for ESRD was observed (relative risk, 0.96). As expected, adjustment for pre-existing hypertension, CKD, rheumatic disease, and diabetes mellitus halved the excess risk for subsequent nephropathy. The sex of the sibling did not appear to alter the observed risk. This study clearly demonstrates that familial aggregation of preeclampsia in Europeans is insufficient to explain the increased risk for subsequent ESRD among preeclamptic patients. Although preeclampsia and ESRD are known to aggregate in families, women with preeclampsia who develop ESRD later in life do so independently from their familial history of preeclampsia. This study is therefore instrumental in demonstrating that preeclampsia alone is an important risk factor for ESRD. Paternal family history of preeclampsia and change in paternity (although the latter may be explained by the length of time between births) can confer increased risk for preeclampsia (9,10,15,16). Cohorts centered on the father as the index subject were also examined in this report.Menwith siblingswho hadpreeclampsia in their first pregnancies had slightly increased risk for ESRD after adjustment for age and marital status. This might suggest that different phenomena occur in males and females, with a slightly increased risk for ESRD amongmales in the presence of a familymember with preeclampsia; this effect could potentially be inherited (biologically mediated) or due to familial aggregation of environmental risk factors. The sex effect was observed along with a higher ESRD event rate in the male-indexed cohort. Section on Nephrology, Wake Forest School of Medicine, WinstonSalem, North Carolina