Midkine release during hemodialysis is predictive of hypervolemia and associates with excess (cardiovascular) mortality in patients with end-stage renal disease: a prospective study

Background In end-stage renal disease, a high cardiovascular risk profile and endothelial damage prevails. The heparin-binding growth factor midkine stimulates neo-angiogenesis in ischemic diseases, coordinates neutrophil influx, and raises blood pressure through stimulated angiotensin synthesis. Methods We determined changes of midkine serum levels during hemodialysis sessions under the assumption that endothelial cell-derived midkine is released. Periprocedural differences (∆midkine) were calculated and correlated with cardiovacular biomarkers and fluid status (clinical assessment, V. cava collapse, comet tail phenomenon), cardiovascular morbidities, mortality rates. Blood was collected before and after dialysis from hemodialysis patients ( n = 171; diabetes: n = 70; hypervolemia: n = 83; both: n = 32). Results Baseline midkine levels were ~ fourfold elevated compared to healthy controls ( n = 100). Further, on average a tenfold rise was detected during dialysis, the extent of which was partially related to non-fractionated heparin application ( r 2 = 0.17). Inter-individual differences were highly reproducible. Hypervolemic patients responded with a less than average rise in midkine levels during dialysis ( p < 0.02), this difference became more obvious with co-existing diabetes ( p < 0.001 for long dialysis-free interval) and was confirmed in an independently enrolled dialysis cohort ( n = 88). In Kaplan Meier survival curves, low delta midkine levels correlated with cardiovascular/overall mortality rates, similar to elevated uPAR levels, whereas other markers (NTproANP, galectin, tenascin-C) were less predictive. Following intervention with successful fluid removal in hypervolemic dialysis patients to optimize fluid homeostasis, midkine values increased ( p < 0.002), which was not observed in patients that failed to decrease weight. Conclusion Thus, for dialysis patients inadequate periprocedural midkine upregulation is linked with hypervolemia and associates with cardiovascular events.