Striking increase in circulating hepatocyte growth factor during enoxaparin-anticoagulated haemodialysis

Jacek Borawski, Beata Naumnik and Michal Mysliwiec

Department of Nephrology and Internal Medicine Medical Academy Bialystok, Poland Email: jborawski{at}post.pl

Sir,

Hepatocyte growth factor (HGF) is a multipotent cytokine of growing importance in tissue development, apoptosis, regeneration and repair of injuries. In chronic haemodialysis (HD) patients, serum HGF levels are increased, directly related to the extent of arteriosclerosis and chronic inflammation, and the prevalence of cardiovascular disease and viral hepatitis, and may stimulate erythropoiesis [1,2]. They also independently predict mortality in dialysis patients [2]. Increased HGF may thus be viewed as a marker of co-morbidity and poor survival, and at the same time as an indicator of the activated body repair in this population.

Recently, we reported in this journal that the use of unfractionated heparin (UFH) vs low molecular weight (LMW) enoxaparin during intermittent HD could be directly predictive of increased serum HGF levels [1]. We also found a direct association between pre-dialysis levels of the cytokine and a dose of UFH. Therefore, we hypothesized that heparin could be a specific stimulus for the HGF release in maintenance HD patients [1]. In the present study, we followed serum HGF levels during dialysis [by enzyme-linked immunosorbent assay (ELISA) from R&D Systems, Inc., Minneapolis MN] in 14 patients anticoagulated with enoxaparin (Clexane, Bellon Rhône-Poulenc Rorer, Montrouge, France). The heparin was injected into the arterial line as a bolus of 40 (20–60) mg (0.70 ± 0.22 mg/kg) at the onset of HD, following the initial rinse of the circuit with 1000 ml of isotonic saline containing 2.0 IU/ml of UFH. The anticoagulation regimen had been employed effectively for at least 2 months prior to the study.

Serum HGF levels were 1.82 (1.20–5.70) ng/ml pre-dialysis, 31.0 (15.4–83.7) ng/ml after 10 min, and 8.97 ± 3.56 ng/ml after 180 min from the start of HD and after enoxaparin injection (Friedman’s ANOVA {chi}2 for the change = 28.0, P < 0.0001). As shown in Figure 1A, HGF strikingly increased by a mean of 1596 ± 650% after 10 min of HD compared with baseline (Wilcoxon’s P = 0.001). After 180 min, it was higher by 349 ± 190% vs pre-dialysis, and lower vs the 10 min level (both P = 0.001). The 10 min percentage increase in HGF (Spearman’s {rho} = 0.594, P = 0.025, Figure 1B) but not that at 180 min ({rho} = 0.268, P = 0.353) significantly correlated with the dose of enoxaparin.



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Fig. 1. Case profiles of serum HGF during enoxaparin-anticoagulated HD (A), and relationship between the percentage increase in HGF after 10 min of HD and dose of enoxaparin (B).

 
This study shows an abrupt and sustained increase in serum HGF during enoxaparin-anticoagulated HD. To our knowledge, the magnitude of the early rise in circulating HGF cannot be compared with any other moiety studied in this clinical setting so far. Similar behaviour of HGF was evidenced previously in non-dialysis subjects receiving i.v. heparin [3,4]. After 5 min following the injection of 3000 IU of UFH, serum HGF increased by as much as 2500% [3]. In another study, the peak increment in circulating HGF in response to administration of the LMW dalteparin at a mean dose of 0.36 mg/kg amounted to ~800% and was noted after 10 min [4]. The HGF increase lasted up to 4 h post-injection [4]. The reason for a rapid increase in circulating HGF due to heparin may be the displacement of the cytokine from heparan sulfate proteoglycans [35]. The prolonged increment in the growth factor may be explained be a lower clearance of HGF–heparin complexes and an enhanced production of the cytokine by heparin [35]. The only study with which to compare our data is by Rampino et al. [5] who also found serum HGF to be increased up to 30 times after 15 min of HD, and still elevated after 240 min. Interestingly, they showed that serum HGF was rising even during heparin-free HD, which was ascribed to the over-dialytic activation of blood mononuclear cells and tissue fibroblasts. However, the increment in HGF was much more pronounced during standard HD. Unfortunately, the authors did not specify either the type or dose of heparin used for HD, or mention whether the heparin-free HD was performed with or without pre-rinsing with heparinized saline [5].

Our data show for the first time that the early increase in serum HGF directly depends on the dose of enoxaparin used for blood anticoagulation during intermittent HD procedures. It implies that heparin may be a modulator of the biological effects of HGF in chronic HD patients, especially as the cytokine also acts as a classic hormone exerting its distant effects in a concentration-dependent manner. The consequences of such marked and prolonged elevations in serum HGF due to repeated heparin administration may be important in HD patients. They deserve further detailed evaluation because HGF augments organ repair but may also propagate cancer metastases due to its angiogenic effects.

References

  1. Borawski J, Mysliwiec M. Serum hepatocyte growth factor is associated with viral hepatitis, cardiovascular disease, erythropoietin treatment, and type of heparin in haemodialysis patients. Nephrol Dial Transplant 2002; 17: 637–644[Abstract/Free Full Text]
  2. Malatino LS, Mallamaci M, Benedetto FA et al. Hepatocyte growth factor predicts survival and relates to inflammation and intima media thickness in end-stage renal disease. Am J Kidney Dis 2000; 36: 945–952[ISI][Medline]
  3. Matsumori A, Ono K, Okada M, Miyamoto T, Sato Y, Sasayama S. Immediate increase in circulating hepatocyte growth factor/scatter factor by heparin. J Mol Cell Cardiol 1998; 30: 2145–2149[CrossRef][ISI][Medline]
  4. Seidel C, Hjorth-Hansen H, Bendz B et al. Hepatocyte growth factor in serum after injection of unfractionated and low molecular weight heparin in healthy individuals. Br J Haematol 1999; 105: 641–647[CrossRef][ISI][Medline]
  5. Rampino T, Libetta C, de Simone W et al. Hemodialysis stimulates hepatocyte growth factor release. Kidney Int 1998; 53: 1382–1388[CrossRef][ISI][Medline]




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