L’utilisation d’héparine en peropératoire des transplantations rénales réduit-elle le risque de thrombose du greffon ?

04 juin 2021

Auteurs : J. Denize, G. Defortescu, D. Guerrot, P. Jeannot, D. Bertrand, J.-N. Cornu, C. Pfister, F.-X. Nouhaud
Référence : Prog Urol, 2021, 8, 31, 531-538




 




Introduction


The prevalence of chronic kidney disease (CKD) is constantly increasing, due to the rise of life expectancy and incidence of risk factors such as diabetes and hypertension [1]. Ideally, the standard treatment for end-stage renal disease (ESRD) is renal transplantation, which improves life expectancy and allows a health-related cost reduction and a better quality of life compared to dialysis [2].


According to the World Health Organization, there were around 2.62 million people treated for ESRD worldwide and the need for dialysis was projected to be double by 2030 [3]. The estimation of the number of patients needing renal replacement therapy (RRT) is around 5 million [4]. In Europe in 2016, the majority of prevalent patients (58%) were receiving haemodialysis, 37% of patients were living with a kidney transplant and 5% were receiving peritoneal dialysis [5].


Depending on the series, vascular complications following renal transplantation are reported ranging from 3 to 15% of the surgical complications depending on the studies with 0.5 to 2% of arterial thrombosis and 0.4 to 6% of venous thrombosis [6, 7, 8]. Thrombosis occur most of the time at the early postoperative period and represent a major risk factor for graft loss even in case of appropriate urgent management [7].


At least two vascular anastomoses are performed during the surgery, which raises the question of the interest of using intravenous heparin injection during the procedure. Heparin is routinely used during vascular surgery procedure to reduce thrombotic complications [9]. During renal transplant, its use differs between surgical teams' habits or even between surgeons but also according to the recipient conditions or the renal graft specificities. To date, no recommendations have been established to guide our practice due to the lack of data in literature to answer the question of heparin benefit.


The purpose of our study was to assess the interest of using intraoperative intravenous heparin during renal transplantation, comparing the incidence of postoperative vascular thrombosis and hemorrhagic complications among recipients.


Materials and methods


Study population


A retrospective study was carried out including every consecutive patient who underwent kidney transplantation at our center between January 2011 and December 2015. Patients receiving long-term anticoagulant treatment or patients with missing perioperative data were excluded. Renal transplantation was performed by several surgeons following the same routine technique as described firstly by Küss in the early 1950's and improved over time [10]. Renal artery and vein were routinely anastomosed on external iliac vessels as well as right kidneys were transplanted in right iliac fossa and left kidneys in ipsilateral fossa. This study was conducted following the principles of the Declaration of Helsinki 1975, as revised in 2013. When heparin was used, it was administered at the dose of 0.5mg/kg before venous clamping. Routinely, some surgeons were using heparin for every transplantation and the others didn't, occasionally this might differ either way at the discretion of the surgeon depending on peroperative ascertainment. For patients on regular antiplatelet treatment, they received postoperative IV heparin for 15 days (aPTT between 1,2-1,3). For those without antiplatelet treatment, no systematic heparin, even prophylactic, was used, unless in case of previous graft thrombosis, or history of thrombosis or thrombophilia factor. In case of graft thrombosis, patients received curative heparin protocol in the postoperative period to reach an aPTT between 2 and 3. This study was conducted in accordance with the ethical standards of the institutional research committee and following the principles of the Declaration of Helsinki 1975, as revised in 2013.


Data collection


For each patient, chart review was performed to collect perioperative data. The age, gender, body mass index (BMI), etiology of CKD, use of antiplatelet treatment, Charlson comorbidity index (CCI), preoperative type of dialysis, immunosuppressive treatment modalities and history of renal graft were collected. A Doppler ultrasound (US) was systematically performed at day one postoperatively. In some cases, if the Doppler US wasn't contributive or in case of strong clinical suspicion of vascular complication, additional MRI or CT angiogram was performed. The presence or absence of postoperative vascular thrombosis on these different imaging tests was collected. Postoperative complications were collected according to Clavien-Dindo classification [11].


Statistical analysis


All data were collected in a standardized electronic data base. Study population was divided in two groups depending on whether they received intraoperative heparin or not. The characteristics and outcomes between the two groups were compared Chi2 test, Student test and Fisher test. The presence or absence of postoperative vascular thrombosis was compared between the two groups, as well as the occurrence of severe hemorrhagic complications (Clavien≥3) or the need for postoperative transfusion. Statistical analyses were performed using MedCalc Statistical Software version 18.9 (MedCalc Software bvba, Ostend, Belgium; www.medcalc.org/; 2018). P -value<0.05 was used to define statistical significance.


Results


Patient's characteristics


In total, 376 consecutive kidney transplantations were performed at our institution during the study period. Among them, 37 patients were on long-term anticoagulant treatment and for 78 patients, intraoperative data about heparin administration were missing. Finally, 261 patients were definitely included in the study. Fifty-one patients received intraoperative IV-heparin and 210 didn't (Figure 1). Patient's characteristics are summarized in Table 1. There was no significant difference between the two groups regarding the age, gender, BMI and the use of antiplatelet treatment. Patients with a Charlson comorbidity index superior or equal to 3 or with a CDK etiology considered at higher risk for renal graft thrombotic complications (diabetic nephropathy, vascular nephropathy, IgA nephropathy...) were comparable. Most of the patients had hemodialysis (78%) and received an immunosuppressive treatment with tacrolimus. For most of them, it was their first renal transplantation (87%).


Figure 1
Figure 1. 

Flow chart specifying in detail the population of the study.




Transplantations characteristics


Transplant characteristics are summarized in Table 2. Living donor transplants were more frequent in the intraoperative heparin group: 24 (47%) versus 12 (6%) for the other group which had more cadaveric donor (P <0.001). The number of right kidneys in right iliac fossa was higher in the group without intraoperative heparin: 90 (43%) versus 9 (18%) in the heparin group (P <0.001) while the number of left kidneys in left iliac fossa was higher in the heparin group (P =0.002). The number of arteries and veins on the graft wasn't different between the two groups. Kidneys from expanded criteria donors were equally represented and the use of perfusion machine for renal transplants wasn't different between the two groups. No difference was observed in recovery of renal function between the two groups (Table 3). Twenty patients (40%) in the heparin group had a delayed recovery of renal function versus 65 (31%) in the group without heparin (P =0.24). No difference was observed between the two groups concerning the need for transplantectomy during the first month after transplantation and the need for dialysis during the first postoperative year.


Patient's outcomes


Three cases of vascular thrombosis were observed in the group with heparin (6%) including 1 case of renal artery thrombosis and 2 cases of venous thrombosis. In the other group, 13 cases of thrombosis were identified: 5 cases of venous thrombosis, including 2 cases with an associated arterial thrombosis and 8 cases of exclusive arterial thrombosis including 5 cases of polar artery thrombosis only. There was no significant difference between the two groups regarding the thrombosis occurrence rate (P =1). These results are summarized in the Table 3.


In the group of patients receiving heparin, 3 patients (6%) developed a hematoma requiring surgical revision vs. 11 (5%) in the group without heparin (Table 3). No significant difference was observed between the two groups regarding such hemorrhagic complications (P =1) as well as no significant difference was found for postoperative need for transfusion (P =0.55) or anticoagulant accident (P =0.35). Rate of macroscopic hematuria was similar between the two groups (2% in the group with heparin versus 6%, P =0.38), as well as the occurrence of lymphocele (2% in the heparin group versus 0%, P =1).


In addition, no risk factor of vascular thrombosis was identified (Table 4). Patients with vascular thrombosis and patients without thrombosis had the same demographic characteristics. Number of patients previously treated by peritoneal dialysis was low in the two groups (6% in thrombosis group and 15% in the other group). Immunosuppressive treatments type didn't differ between the two groups, most of the patients received a treatment including tacrolimus rather than cyclosporine. Origin of renal graft and its position as well as the number of graft vessels wasn't significantly different between the groups. Times of cold and warm ischemia were also similar.


Finally, regarding the graft function (Table 5), delayed recovery of renal function and number of transplantectomy were significantly more common for patients encountering a vascular thrombosis (respectively 69% versus 30%, P =0.001 and 38% versus 0.4%, P <0.001).


Discussion


To our knowledge, we report here the results obtained from one of the largest cohort to date on this topic [12, 13]. We didn't find any statistically significant difference for vascular thrombosis incidence between patients who received intraoperative heparin and those who didn't. However, at the same time, heparin wasn't associated to a higher rate of complications, especially hemorrhagic events.


Among the limited number of studies available on this subject, the largest study was published recently by van den Berg et al. including about 2000 kidney transplantations [12]. It was a retrospective multicentric cohort analysis including all adult kidney transplantations recipients, regardless of the type of donors and prior antithrombotic therapy. Among all the patients included, 195 received intraoperative heparin with no statistical difference found regarding the risk of thrombosis (P =0,71) or the risk of bleeding (P =0,15).


Another large study was from Mohan et al., assessing the role of IV heparin during renal transplantation on a cohort 200 patients [13]. One group received 5000 units of heparin intravenously just before vascular clamping and was compared to a control group without intraoperative heparin. The two groups were comparable for age, primary or re-transplantation, donor age and cold ischemia time. All patients received a triple immunosuppressive therapy consisting of cyclosporine, prednisone and azathioprine. There was no significant difference between the two groups in terms of incidence of renal graft thrombosis (6% in the group with heparin and 4% in the other group). Interestingly, our findings were confirming these results.


Regarding hemorrhagic complications, especially hematoma requiring a surgical revision, there was no significant difference between the two groups. There was also no difference in terms of need for transfusion, suggesting that intraoperative heparin is not associated with a significant increased risk of hemorrhagic complications. These findings were contrasting with those from previous retrospective studies which suggested a higher rate of transfusion need for patients receiving intraoperative heparin or early postoperative heparin [13, 14, 15, 16, 17]. It has to be mentioned that in our study, patients with long-term anticoagulant treatment were excluded unlike these other studies. This long-term anticoagulant treatment might have introduced bias regarding the assessment of the thrombosis event and could explain that we didn't find similar results in our homogeneous cohort reflecting only the role of intraoperative use of heparin. Also, the heparin dose used may differ from a study to another, which may be another cause for the differences in the results we reported here.


Regarding the long-term graft function outcomes, only a few data are available related to intraoperative heparin and graft survival. However, we already know that renal graft survival is significantly decreased in case of renal vascular thrombosis with an important risk of early graft dysfunction and transplantectomy [7]. About the rate of renal graft survival at one year, no difference was observed between the two groups in terms of number of transplantectomies and need of new dialysis. As expected, patients encountering a vascular thrombosis had more delayed recovery of renal function and a higher risk of transplantectomy.


Furthermore, we did not identify perioperative risk factors of vascular thrombosis. Conversely, in a recent literature review, Keller et al. identified several risk factors as age with donors over 60-years-old (expanded criteria donors) and under 6 years at higher risk and pediatric recipients under 6 years [18]. In our cohort, donors over 60-years-old weren't identified as a risk factor for thrombosis, this difference could be due to the size of our cohort compared to this literature review. Regarding the pediatric recipient and donors, as our department is adult urology, we couldn't include pediatric cases to assess this risk factor. In addition, per- and postoperative hemodynamic instability, peritoneal dialysis, diabetic nephropathy, history of thrombosis, cold ischemia time over 24 hours and multiple donor arteries have also been described as possible risk factors for thrombosis [12, 18]. Again, we didn't found similar results in our cohort; however, as these events as well as vascular thrombosis were rare, it potentially led to a lack of power to properly assess the correlations between them. To this, we aimed to assess potential intraoperative risk factors of vascular thrombosis due to the surgery itself and its complexity: a renal graft and renal vessels malposition, a stenotic vascular anastomosis, intraoperative vessels damages or extraneous vascular compression. Eventually, we didn't confirm these risk factors. However, the retrospective nature of the study limited the possibility to collect proper standardized data regarding the quality of the graft vessels. This limitation was also present in the prior studies explaining the complete lack of data about this.


The prothrombotic effect of cyclosporine was described in several prior studies [19]. Its mechanism relies on endothelial toxicity by fibrinolysis impairment, procoagulant mechanisms activation and platelet control alteration. Only a limited number of patients received this immunosuppressive treatment in our study, this can explain that no difference was observed for incidence of thrombosis according to immunosuppressive treatment. Immunosuppressive treatments including tacrolimus were mostly used while other treatments were administered as part of protocols. Tacrolimus showed an advantage over cyclosporine related to renal graft survival as reported by Graff et al. (2% versus 9%, P =0.003) [20].


As mentioned above, our results based on a larger study are consistent with the current data from the literature which are not supporting the use of intraoperative heparin to reduce the risk of vascular thrombosis. To date, due to the lack of evidence, there is no recommendation about heparin administration during renal transplantation. Indeed, European Association of Urology guidelines are limited to living donors graft and advocate to not systematically administer preventive postoperative heparin for recipients except for graft on vascular prosthesis [21].


Regarding the recipient thrombotic risk, investigation for thrombophilia wasn't systematic for the patients without thrombotic history, as to date there is no evidence supporting it. Regarding renal transplants characteristics in our study, patients with intraoperative heparin had a larger number of living donor's transplants. This result is related to the nearly constant use of intraoperative heparin for recipients of living donor's kidneys during this period due to surgeon habits. This data also explains the difference between left and right renal transplants between the two groups, kidney transplants issued from living donor being most of the time left kidneys.


We have to acknowledge some limitations to this study. First, several limitations are due to its retrospective nature. As already mentioned, the cohort size, especially regarding the heparin group could have led to a lack of power limiting the assessment of thrombosis risk factors. In addition, the indication for intraoperative heparin was at the discretion of the surgeon at the time of the surgery. Usually, some surgeons used heparin systemically and the others did not. However, some indications for heparin could have been led by intraoperative conditions due to the patient or the graft with no possibility to access to this data due to the retrospective nature of the study.


In conclusion, our study suggests that intraoperative IV heparin doesn't improve the risk of vascular thrombosis following renal transplantation these results don't support the routine use of heparin in these indications. However, intraoperative IV heparin was not associated with higher rate of hemorrhagic complications suggesting that heparin can be safely used if required in some selected patient at higher risk of thrombosis. These conclusions need to be confirmed by a prospective study.


Disclosure of interest


The authors declare that they have no competing interest.




Table 1 - Characteristics of the population.
  No intraoperative heparin
(n =210) 
Intraoperative heparin
(n =51) 
P  
Age (mean±sd)  53±15  50±15  P =0.2 
Gender 
Female  82 (39%)  22 (43%)  P =0.59 
Male  128 (61%)  29 (57%)   
BMI (mean±sd)  25.31±4.6  25.34±4.6  P =0.79 
Antiplatelet treatment  50 (24%)  15 (29%)  P =0.4 
Charlson comorbidity index 
≥ 84 (40%)  17 (33%)  P =0.38 
Chronic kidney disease at risk of thrombosis  101 (48%)  25 (49%)  P =0.69 
Modality of dialysis 
Hemodialysis  165 (79%)  38 (75%)  P =0.75 
Peritoneal dialysis  29 (14%)  9 (18%)   
No dialysis  16 (7%)  4 (7%)   
Immunosuppressive treatment 
Tacrolimus based  191 (91%)  47 (92%)  P =
Cyclosporine based  14 (6%)  3 (6%)   
Other  5 (3%)  1 (2%)   
Renal graft number 
1st  180 (86%)  47 (92%)  P =0.26 
≥ 30 (14%)  4 (8%)   





Table 2 - Renal transplants characteristics.
  No intraoperative heparin
(n =210) 
Intraoperative heparin
(n =51) 
P  
Type of donor 
Living donor  12 (6%)  24 (47%)  P <0.001 
Brain-dead donor  197 (94%)  26 (51%)   
Circulatory death donor  1 (2%)   
Renal graft position 
Right in RIF  90 (43%)  9 (18%)  P <0.001 
Right in LIF  20 (10%)  5 (10%)   
Left in RIF  16 (7%)  5 (10%)  P =0.61 
Left in LIF  83 (40%)  32 (62%)  P =0.002 
Multiple arteries (≥2)  33 (16%)  8 (16%)  P =0.99 
Multiple veins (≥2)  8 (4%)  3 (6%)   
Expanded criteria donorsa  91 (43%)  17 (33%)  P =0.19 
Perfusion machine  60 (29%)  10 (20%)  P =0.19 



Légende :
RIF: right iliac fossa; LIF: left iliac fossa. Characters in bold: statistically significant results.

[a] 
Expanded criteria donors=allografts from deceased donors older than 60 years of age and those from donors aged 50-59 years old with at least two of the followings characteristics: history of hypertension, serum creatinine greater than 1.5mg/dL or cerebrovascular as the cause of death (definition of United Network for Organ Sharing).


Table 3 - Transplantation outcomes according to the intraoperative IV heparin status.
  No intraoperative heparin
(n =210) 
Intraoperative heparin
(n =51) 
P  
Vascular thrombosis  13 (6%)  3 (6%)  P =
Artery   
Vein   
Polar artery   
Hematoma requiring surgical revision (Clavien 3b)  11 (5%)  3 (6%)  P =
Postoperative transfusion (Clavien 2)  57 (27%)  16 (31%)  P =0.55 
Lymphocele  4 (2%)  0 (0%)  P =
Complicated macroscopic hematuriaa  5 (2%)  3 (6%)  P =0.38 
Anticoagulant accident  1 (0.4%)  1 (2%)  P =0.35 
Recovery of renal function 
Slowb  34 (16%)  4 (8%)  P =0.24 
Delayedc  65 (31%)  20 (40%)   
Transplantectomy during the first year  5 (2%)  2 (4%)  P =0.33 
Back to dialysis (1-year follow-up)  17 (8%)  3 (6%)  P =



[a] 
Complicated macroscopic hematuria=hematuria requiring blood transfusion and/or intravesical irrigations or surgical management (Clavien>=2).
[b] 
Slow recovery of renal function=creatinine spontaneously≥250μmol/L during the first 7 postoperative days.
[c] 
Delayed recovery of renal function=requiring at least one dialysis session during the first 7 postoperative days.


Table 4 - Risk factors of vascular thrombosis.
  Vascular thrombosis
(n =16) 
No vascular thrombosis
(n =245) 
P  
Recipient age (mean±sd)  52±16  53±15  P =0.48 
BMI (mean±sd)  25.4±4.8  25.3±4.6  P =0.28 
Gender 
Female  9 (56%)  95 (39%)  P =0.17 
Male  7 (44%)  150 (61%)   
Antiplatelet treatment  6 (37.5%)  59 (24%)  P =0.23 
Charlson comorbidity index≥ 7 (44%)  94 (38%)  P =0.69 
Chronic kidney disease at risk of thrombosis  8 (50%)  118 (48%)  P =0.89 
Modality of dialysis 
Hemodialysis  13 (81%)  190 (78%)  P =0.51 
Peritoneal dialysis  1 (6%)  37 (15%)   
No dialysis  2 (13%)  18 (7%)   
Renal graft number 
14 (87%)  212 (87%)  P =
≥ 2 (13%)  33 (13%)   
Immunosuppressive treatment 
Tacrolimus based  13 (81%)  225 (92%)  P =0.17 
Cyclosporine based  2 (13%)  15 (6%)   
Other  1 (6%)  5 (2%)   
Donor 
Brain-dead  13 (81%)  210 (86%)  P =0.54 
Living donor  3 (19%)  33 (13%)   
Circulatory death donor  2 (1%)   
Kidney 
Right in RIF  7 (44%)  92 (38%)  P =0.81 
Right in LIF  1 (6%)  24 (10%)   
Left in RIF  21 (8%)   
Left in LIF  8 (50%)  107 (44%)   
Number of arteries≥ 3 (19%)  25 (10%)  P =0.39 
Number of veins≥ 1 (6%)  10 (4%)  P =0.51 
Polar arteries  4 (25%)  34 (14%)  P =0.26 
Perfusion machin  4 (25%)  66 (27%)  P =
Expanded criteria donor  8 (50%)  100 (41%)  P =0.47 
Intraoperative heparin  3 (19%)  48 (20%)  P =
Duration of cold ischemia (hours)  14.2  14.2 P =0.37 
Duration of warm ischemia (minutes)  45.6  44  P =0.23 





Table 5 - Renal graft function according to the presence of vascular thrombosis.
  Vascular thrombosis
(n=16) 
No vascular thrombosis
(n=245) 
P  
Recovery of renal function 
Slow  0 (0%)  38 (16%)  P =0.16 
Delayed  11 (69%)  74 (30%)  P =0.001 
Transplantectomy  6 (38%)  1 (0,4) %  P <0.001 




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