Year : 2007 | Volume
: 18 | Issue : 2 | Page : 177--185
Successful Kidney Transplantation Does not Reverse the Coagulopathy in Patients with Chronic Renal Failure on Either hemo or peritoneal dialysis
A Ballow1, AMA Gader2, S Huraib1, A Mitwalli3, F Al-Suleimani3, J Al-Wakeel3,
1 Division of Nephrology, King Fahad National Guard Hospital, Riyadh, Saudi Arabia
2 Coagulation Laboratory, King Fahad National Guard Hospital, Riyadh, Saudi Arabia
3 Division of Nephrology, King Khalid University Hospital, Riyadh 11461, Saudi Arabia
King Khalid University Hospital P.O. Box 2925, Riyadh 11461
There is wide disagreement about the measurement of various hemostatic parameters in patients with chronic renal failure (CRF) concerning treatment with either hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). This study aims to characterize the coagulopathy in patients with CRF both before initiating dialysis, when the patients are expected to have a steady hemostatic state, and after starting regular HD or CAPD. The measurements were repeated in a group of patients who received a successful renal transplant to see whether the coagulopathy associated with CRF would be corrected by this lasting therapy. The study, which was mainly cross-sectional and prospective, included two groups: 49 patients with CRF with their age ranging from 17 to 67 years were divided as follows: those on regular HD (n=20), CAPD (n=9) and patients after transplant (n=20). The tests were also done on 34 healthy controls. Significant hyper-fibrinogenemia was recorded in all three study groups. The HD group showed significant elevation in the plasma levels of AT III and total protein S, and a significant reduction in free protein S and protein C, when compared with healthy controls. These inhibitors, except total PS, displayed similar fluctuations in the CAPD group. In the transplant patients, there was significant elevation of AT III and total protein S, a reduction in free PS, and no significant changes in PC levels. A significant elevation was found in the levels of F1+2, TAT and D-Dimer in HD and in transplant patients, when compared with controls. In CAPD patients, only D-Dimer levels showed a significant increase. The tPA and PAI-1 levels in the three study groups were similar to the control group. Our study revealed significant activation of the hemostatic system, more pronounced in patients on HD than CAPD. This coagulopathy remained only partly corrected following successful kidney transplantation.
|How to cite this article:|
Ballow A, Gader A, Huraib S, Mitwalli A, Al-Suleimani F, Al-Wakeel J. Successful Kidney Transplantation Does not Reverse the Coagulopathy in Patients with Chronic Renal Failure on Either hemo or peritoneal dialysis.Saudi J Kidney Dis Transpl 2007;18:177-185
|How to cite this URL:|
Ballow A, Gader A, Huraib S, Mitwalli A, Al-Suleimani F, Al-Wakeel J. Successful Kidney Transplantation Does not Reverse the Coagulopathy in Patients with Chronic Renal Failure on Either hemo or peritoneal dialysis. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2022 Jun 25 ];18:177-185
Available from: https://www.sjkdt.org/text.asp?2007/18/2/177/32306
Patients with chronic renal failure (CRF) are at increased risk of developing either of two hemostatic defects. First and more commonly is bleeding diathesis,, and this has been ascribed to a defect in primary hemostasis ,, with conflicting reports on the contribution of plasma hemostatic factors; ,,,,,,, and second, a thrombotic tendency that features thrombosis of the vascular access as well as a greater tendency to develop atherosclerotic cardiovascular disease ,, which is the leading cause of morbidity and mortality in uremic patients.
Earlier investigators have studied the effect of renal replacement therapies on the hemostatic abnormalities of CRF. Erythropoietin, for example, causes further worsening of these hemostatic abnormalities. Furthermore, dialysis whether hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD), causes some improvement of the hemostatic disturbances, although more recent studies have found evidence of thrombin generation and fibrin formation with no difference in this respect between either of the two therapies.[ 15],,,, It was also presumed that renal transplantation would reverse these hemostatic disturbances and normalize their levels. However, in the face of numerous disagreements, the field is still open for further studies.
This study aims to achieve the following objectives:
a) To characterize the hemostatic abnormallities, specifically markers of hemostatic activation and natural inhibitors of coagulation and fibrinolytic parameters in patients with CRF on either of the two forms of replacement therapies, HD or CAPD; and
b) To see whether kidney transplantation, the lasting treatment for CRF, will normalize the changes in these hemostatic markers.
Materials and Methods
The patients in this study were randomly selected from the Out-patient Nephrology Clinic, Hemodialysis, and Transplant Clinics at the King Fahad National Guard Hospital as well as In-patients and the Out-patient Clinic for Peritoneal Dialysis at the King Khalid University Hospital, Riyadh. Patients were split into three groups as follows:
a). Hemodialysis Group (n=20)
The HD group was comprised of 13 males, aged 19 to 67 years (mean + SD: 47.2 + 15.8), and seven females, aged 15 to 69 years (mean + SD: 51.4 + 18.6). All patients were on recombinant erythropoietin (rHuEPO), the dose of which varied between 1,000 to 7,000 units once to twice weekly). Seventeen of the 20 patients were also on iron succinate supplement, depending on their hemoglobin level. None of these patients had any history of fistula thrombosis during the past year.
b). Peritoneal Dialysis Group (n=9):
This group consisted of four females and five males. The age of the females ranged from 40 to 71 years (mean + SD: 57.7+13.5), while in males, the age ranged from 18 to 36 years (mean + SD: 25.2 +7.7). c). Transplant Group (n=20)
In this group, 14 were males aged 17 to 53 years (mean + SD: 29.8 + 9.5) and six were females aged 14 to 55 years (mean + SD: 29.5 + 14.6). All patients were taking immunosuppressive drugs (prednisone, azathioprine and cyclosporine). The kidneys were obtained from living related donors in three patients, living non-related donors in six patients and cadaver donors in 11 patients.
The Control Group (n=34)
This group consisted of apparently healthy males (23) and females (11) that were ageand sex- matched with the study patients.
Blood Collection and Processing
Venous blood samples were collected and delivered directly into vacutainer tubes containing sodium citrate (0.129 M) to give a blood:citrate ratio of 9:1. Proper mixing of blood and anticoagulant was attained by gentle inversion. In patients on dialysis, the blood samples were collected before starting the dialysis procedure or at least two days after the last dialysis session. The blood samples were transferred without delay (within 2 hours of collection) to the coagulation laboratory. Platelet-poor-plasma (PPP) was prepared by centrifuging the samples at 3,000 rpm (1,000G relative centrifugal force) for 15 minutes in a refrigerated (4-66 C) centrifuge. Plasma was separated using plastic pipettes, and aliquots of plasma were immediately stored at - 800 C until analysis at a later date.
Plasma Fibrinogen: This was measured by a turbidometric method.
Hemostatic activation markers: Thrombinantithrombin complex (TAT Complex) and prothrombin fragment 1+2 (F1+2) were measured by enzyme immunoassay (Dade Behring, Germany) while D-Dimer was measured by enzyme immunoassay (Diagnostica Stago, France).
Natural coagulation inhibitors: Antithrombin III (ATIII) activity was measured by the colorimetric assay (The Stachrom kits, Diagnostica Stago, France); protein-C assay by the Asserachrom protein-C test kit enzyme immunoassay (Diagnostica Stago, France); protein-S Assay: (total and free) by the one step enzyme immunoassay using the Asserachrom total and free protein-S kits (Diagnostica Stago, France).
Tests of fibrinolysis: Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-I (PAI-1) were both measured by the enzyme immunoassay assayed by the Asserachrom kits, (Diagnostica Stago, France).
Results are expressed as the mean + standard deviation (X + SD). The unpaired Student's ttest was used to compare the significance of the differences in measurements of the patient groups. A P value of 0.05 or less was considered significant.
The results of the tests pertaining to fibrinogen and natural coagulation inhibitors are given in [Table 1]. The levels of plasma fibrinogen and the natural coagulation inhibitors, AT III and free PS, were significantly raised in patients on HD, CAPD and after transplantation when compared with the control group. The levels of total PS were significantly elevated in patients on HD and in those after transplantation while the levels in patients on CAPD were similar to the control group. The PC levels were significantly decreased in HD and CAPD patients when compared with the control group, while there was no difference between the transplanted and the control groups.
The details of the levels of the markers of activation of coagulation in the three groups are given in [Table 2]. The F 1 + 2 levels showed significant increase in the HD and transplant groups, while there was no difference in the CAPD group when compared with the control group. The TAT levels also showed significant increase in the HD and transplant groups, while there was no difference in the CAPD group when compared with the control group. The D-Dimer levels showed significant increase in the HD, CAPD and transplant groups when compared with the control group.
The details of the tests related to the fibrinolytic system in the three study groups and the control group are given in [Table 3]. The tPA levels were significantly decreased in HD patients when compared with the control group. No significant differences were noted between the CAPD and transplant groups when compared with the control group. The levels of PAI-1 in the HD and CAPD groups were comparable to the levels in the control group; however, in the transplant group, the PAI-1 levels were significantly elevated.
The results of this study show that patients with CRF on HD have more severe hemostatic abnormalities than those on CAPD. Some, but not all, of these abnormalities are corrected in patients who undergo successful kidney transplantation.
In the current study, the hyperfibrinogenemia noted in the CRF patients on HD or CAPD is consistent with many earlier reports.,, However, few other authors , , have reported the mean plasma fibrinogen concentration to be normal in HD patients. Additionally, in the current study, transplant patients demonstrated significant increase in plasma fibrinogen levels when compared to the normal controls, and this conforms with the earlier report of Kobayashi et al. As fibrinogen is an acute phase reactant, this finding indicates that an inflammatory process is in progress in CRF patients on HD or CAPD as well as in kidney transplant patients.
The natural coagulation inhibitors
Many investigators ,,, have reported reduction in the AT III concentration in patients on HD and this decrease was ascribed to heparin therapy. In the current study in which the blood samples were collected 48 hours after the last HD session when the action of heparin is over, we recorded elevated AT III. A few other authors found no remarkable change in AT III levels., Lai et al  found the levels of both antigenic and functional activity of AT III comparable to healthy control levels before and after HD.
We also found elevated levels of plasma AT III in patients on CAPD as well as those who had received successful kidney transplants and this disagrees with many earlier reports, which recorded AT III levels similar to healthy controls in these two groups. ,,
Free and total protein S
In the present study, there was a significant reduction in the levels of the physiologically active free protein S in the three patientgroups; this is in line with the results of earlier reports in HD patients. ,, Loss of free PS antigen during HD is possible but unlikely, as the natural coagulation inhibitors were not detected in the dialysate,  leaving consumption to be a possible mechanism to account for the drop in free PS levels. A third possibility could be an elevation in the levels of C4b-binding protein that forms a complex with free PS; i.e., a redistribution of the plasma protein S pool with a change of active free to inactive, bound PS. In CAPD patients, previous reports on free PS levels have shown reduction, increase 7 and similar levels when compared with healthy controls.
On the other hand, we found the levels of total PS to be significantly higher in HD patients than in normal healthy controls, and this agrees with the results of others. ,,,, This increase can be explained by overproduction of this protein by the liver to compensate for loss/consumption of the free form of the inhibitor. The daily loss of PS through the urinary and peritoneal routes was found to be significantly greater than the urinary loss alone.
The levels of plasma total PS antigen have been reported to be significantly higher in CAPD patients than in normal controls ,, although the present study showed normal total PS in CAPD patients. In transplant patients, we recorded highly significant elevation of total PS; this probably reflects excessive production of this protein by the liver.
Protein C (PC)
In the current study, there was a significant reduction of protein C levels in patients on HD and CAPD, which is in agreement with many earlier studies ,, in HD patients; however, both normal  and elevated levels  of PC have been previously reported. In transplant recipients, Vaziri et al  found significant elevation of PC concentrations, which is in contrast to our finding of no significant changes in PC in these patients.
Markers of activation of coagulation (F1+2, TAT and D-Dimer)
The clinical significance of the determination of F1+2, TAT and D-Dimer is to provide indirect evidence of in vivo activation of the hemostatic system, i.e., thrombin generation (F1+2, TAT) and/or fibrin formation (DDimer). In the current study, we found significant increases in the levels of F1+2, TAT and D-Dimer in both HD and transplant patients. This agrees with many recent studies.,,, It was proposed that the increased volume of blood coming in contact with an artificial surface during HD results in the activation of the clotting system and it is possible that activation of hemostasis extends beyond the immediate duration of the HD procedure. There is also the possibility of the lack of renal clearance of these hemostatic activation markers.
In contrast with earlier reports , of elevated levels of F 1+2 and TAT in CAPD, in the current study there was no significant elevation in the levels of either marker. However, our finding of elevated levels of D-Dimer in CAPD patients, which is in line with another recent report, reflects, if anything, excessive fibrin formation and its subsequent digestion by secondary fibrinolysis in vivo.,,,, In the case of the CAPD procedure, it is presumed that there is high intra-peritoneal fibrin formation, not only during peritonitis but also in clinically stable CAPD. 
It is of interest to note that in transplant patients there was also evidence of hemostatic activation on the basis of elevation of both F1+2, TAT and D-Dimer levels. Earlier studies have reported elevated levels of D-Dimer  in transplant patients on long-term cyclosporine.
The fibrinolytic System
Tissue Plasminogen Activator (tPA)
tPA is synthesized and stored in endothelial cells from where it is released into the blood stream. In this study, the level of tPA was within the normal range in HD, CAPD and transplant patients when compared to the normal controls, which is in line with some earlier studies in HD  as well as CAPD  patients. These findings disagree with the results of others who reported significant increase in tPA levels, but at the end of HD. Earlier Vaziri et al. reported that renal transplant recipients treated with long-term cyclosporine showed an increased concentration of tPA.
Plasminogen Activator Inhibitor Type-1(PAI-1)
Our study showed PAI-1 levels in the HD, CAPD and transplant patients to be similar to healthy controls, and this supports many earlier studies. ,[ 9],[ 10],, In contrast, Goedde et al., reported high blood levels of, PAI-1 during CAPD.
It is of interest to add here that a rise in PAI-1 in the dialysate was demonstrated , and this suggests a route for the loss of this inhibitor in CAPD patients. The conflicting data on fibrinolytic parameters in uremic patients was also frequently highlighted in the literature and was ascribed to many factors,  including the wide variability in the study design (especially the timing of blood samples in relation to the type and duration of the dialysis) or differences in laboratory assays and also to variation in patient characteristics such as age, underlying disease or cause of CRF.
It is known that thrombo-embolic complications, atherosclerosis and cardiovascular disease determine to a great extent, the long-term survival of renal transplant recipients., In the present as well as many earlier studies, ample evidence was presented in favor of the existence of a prothrombotic state in the form of hyperfibrinogenemia, elevated levels of hemostatic activation markers and reduced free protein S. However, we noted with much interest that impaired fibrinolysis due to elevated concentrations of PAI-1 was frequently reported in transplant recipients,,, as well as in CRF patients on long-term HD or CAPD. ,,, None of our study patients showed any evidence of inhibited fibrinolysis.
It is of interest to note here that a recent study in renal transplant recipients observed elevated PAI-1 levels with long-term steroid therapy and that steroid-free immunosuppression resulted in a decrease in circulating PAI-1 levels. Similarly, another study also found elevated PAI-1 levels in association with the administration of cyclosporine but PAI-1 levels dropped when patients were put on azathioprine instead. As our transplant patients are on both steroids and azathioprine, but had normal PAI levels, we can assume that this feature could be an ethnic characteristic of our patients that protects them against the known cardiovascular/thrombotic risks associated with renal transplantation.
The results of this study led us to conclude that CRF is associated with hemostatic abnormalities in the form of hyperfibrinogenemia as well as enhanced activetion of hemostasis with evidence of thrombin generation and fibrin formation, which is most pronounced in HD and less so in CAPD, but persists in transplant patients. Also, the presence of normal fibrinolytic activity could be an effective protective mechanism against atherosclerosis, cardiovascular disease and thromboembolismassociated renal transplantation.
We are grateful to the technicians in the Coagulation Laboratory, College of Medicine (Mohamed A. Hamid, Logman A. Gasmel Sid and Malou Casi for their technical help, and Mrs. Farah Chatila for her secretarial help). This study was supported by a grant from King Abdul Aziz City for Science and Technology (KACST), Riyadh.
The authors declare no Conflict of Interest in the conduct of this study.
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