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Pregnancy-associated plasma protein-A predicts survival in end-stage renal disease—confounding and modifying effects of cardiovascular disease, body composition and inflammation

Background
High pregnancy-associated plasma protein-A (PAPP-A) levels are linked to atherosclerosis and associate with increased mortality in prevalent dialysis patients. We investigated associations of PAPP-A, measured at dialysis initiation, with cardiovascular disease (CVD), CVD risk factors and mortality in incident dialysis patients, and explored if body composition and inflammation modulated these associations.


Methods
Baseline plasma PAPP-A levels, inflammation biomarkers and body composition, using dual-energy X-ray absorptiometry, were measured in 286 incident dialysis patients. Primary outcome was survival during 60 months follow-up. Quantile (median) regression was used for cross-sectional analysis and Kaplan-Meier diagrams and Cox proportional hazards regression for survival analysis.


Results
In cross-sectional analysis adjusted for age and sex, PAPP-A levels were associated with lean tissue index (LTI) and high-sensitivity C-reactive protein (hsCRP) but not with fat tissue index (FTI) or history of CVD. In a model also including diabetes mellitus (DM), the association with LTI did not remain statistically significant. When adjusted for cardiovascular risk factors and body composition, higher PAPP-A levels showed a moderate but significant association [hazard ratio (HR) = 1.2, 95% confidence interval (CI): 1-1.4, P = 0.04] with mortality. When also including hsCRP the association was attenuated (HR = 1.2, 95% CI: 0.99-1.4, P = 0.06). In survival analysis, interactions with PAPP-A on the multiplicative scale were found for hsCRP (HR = 1.6, 95% CI: 1.2-2.2, P = 0.004) and DM (HR = 1.6, 95% CI: 1.1-2.2, P = 0.01) and with DM and FTI on the additive scale.


Conclusions
Higher PAPP-A levels are associated with worse survival in incident dialysis patients following adjustment for established cardiovascular risk factors and body composition indices, but not clearly so when adjusted for hsCRP. Inflammation, body composition (FTI) and DM were found to be potential effect modifiers for the observed moderate association of PAPP-A with survival.