Activation of hepatocyte growth factor/activin A/follistatin system during hemodialysis: role of heparin.

BACKGROUND

Hepatocyte growth factor (HGF), activin A, and follistatin compose an organotrophic system that may be modulated by heparin. We prospectively studied the effects of unfractionated heparin (UFH) versus low-molecular-weight heparin (LMWH) enoxaparin-anticoagulated hemodialysis on plasma levels of the cytokines.

METHODS

The factors were measured by immunoassays in 25 chronic hemodialysis patients at the start and at 10 and 180 minutes of the hemodialysis procedure anticoagulated with bolus enoxaparin. Then, the patients were randomized to either receive a bolus and infusion of UFH or to continue LMWH, and were reexamined after 12 weeks.

RESULTS

Predialysis HGF and follistatin were increased (both P < 0.0001), while activin A was normal in hemodialysis patients. Baseline HGF directly correlated with activin A in hemodialysis subjects (P=0.004). In healthy controls, it was positively associated with follistatin (P=0.001). Both HGF and activin A were markedly increased at each interval of enoxaparin-anticoagulated hemodialysis, and follistatin was increased at 10 minutes (all P < 0.0001). The early increments in HGF and follistatin directly depended on the dose of enoxaparin (both P < 0.030). Remarkably, the rise in activin A was inversely associated with the predialysis level of the cytokine (P < 0.0001). The actions of UFH resembled those of LMWH, although the releasing effects on the growth factors were not dose-dependent. The switch from LMWH to UFH resulted in a significant increase in over-dialysis HGF, a fall in follistatin, and no change in activin A.

CONCLUSION

HGF/activin A/follistatin system is activated and disturbed in chronic hemodialysis patients, including depletion of tissue stores of activin A. Type and dose of heparin used during hemodialysis procedures profoundly influence this pleiotropic system, and may thus modulate vital body functions and course of critical diseases.