Current practice of antithrombotic prophylaxis in pediatric kidney transplantation—Results of an international survey on behalf of the European Society for Paediatric Nephrology

Renal graft thrombosis (RGT) is one of the main causes for early graft loss in pediatric kidney transplantation (KTx). Despite the lack of evidence‐based recommendations, antithrombotic prophylaxis (aP) is used to prevent RGT.


| INTRODUC TI ON
Renal transplantation is the treatment of choice for children and adolescents with end-stage renal disease. 1 Although transplant survival rates have markedly improved over the last decades, renal graft thrombosis (RGT) remains a significant cause of early graft loss in pediatric kidney transplantation (KTx). 2 Renal graft thrombosis occurs mostly within the first week following KTx. 3 The reported incidence of RGT varies between 2.3% and 5.1%, mainly due to differences in study populations and associated risk factors. 2,4 The available evidence does not allow a quantitative differentiation of RGT into arterial or venous thromboses. 5,6 The risk for developing a thrombotic episode due to modifiable and non-modifiable risk factors seems to be higher in pediatric than in adult renal transplantation. [7][8][9] Hence, antithrombotic prophylaxis (aP) with anticoagulants and antiplatelets is widely used to prevent RGT in pediatric KTx. [10][11][12][13] To date, an evidence-based management strategy is still lacking. 10,11,14,15 Thus, neither recommendations nor consensus guidelines on the use of aP are available, and the limited data have to be extrapolated from the adult population. 16 For that reason, an online survey was designed to investigate current practice of aP management strategies in children and adolescents <18 years undergoing KTx.

| Study design
The electronic, questionnaire-based survey (SurveyMonkey comprehensive information about aP including type of anticoagulants and antiplatelets, timing, dosage, mode of application, monitoring, and selection criteria of aP (Supporting Information S1).
The questionnaire was tested in advance by three physicians for the following aspects: clarity, utility, and redundancy. Changes were conducted following the suggestions. The adapted survey was finally tested by another five physicians.
An invitation to complete the survey and a reminder were sent to all ESPN members (n = 518 [state 12/2019]) with provided information about the objective of the study, the investigators involved and the link to the survey website (Supporting Informations S2 and S3).
The research project was not approved by an ethics committee, because the study neither involved patients directly nor was any specific patient data required.

| Study duration and study population
The survey was carried out between July 10, 2019 and January 16,

2020.
Overall, 108 responses were retrieved. After elimination of double (n = 17) and triple data entries (n = 3), 85 responding pediatric nephrology centers were identified. Responders who did not perform renal transplantation in the pediatric population <18 years (n = 4) or could not be assigned to a particular institution (n = 1) were excluded from the analysis. Finally, 80 pediatric KTx centers were included for data evaluation.

| Statistical analyses
The responses were collected in an electronic database and checked before the final analysis. Double and triple responses from one center were combined into a single answer. The overall completion rate of the questions within the entire survey was 84% (67/80) excluding two mandatory questions (Q24 and Q30) both completed by <50% of the responders. The statistical analyses were conducted and reported based on the number of total answers for each question. Details of data completion including missing and valid data for all items are provided in the Supporting Information S4. If data were missing or ambiguous, responders were contacted via email for further information.
Data were analyzed using the statistical package SPSS for Windows, release 21 (IBM Corp.). Differences between subgroups were calculated using the Mann-Whitney U test for continuous variables, and P < .05 was considered significant. Data were checked for normal distribution according to the Kolmogorov-Smirnov test.
Continuous variables following a normal distribution were expressed as mean and standard deviation, and non-normally distributed as median and range. Categorical variables were expressed as frequencies and percentages.

| Demographic and institutional characteristics
The 80 participating centers originated from 37 countries (84%  were the main reasons for selective screening (Table 1). An overview including all thrombophilia screening parameters is displayed in

| General aspects of antithrombotic prophylaxis
A protocol for aP was available in 81% (60/74) of all participating centers. A stratified risk assessment for aP was reported by 70%      6 to <12 years 1 3

12-18 years 1 3
Surgical re-intervention 9 29 Re-kidney transplantation 4 13 Deceased donor kidney transplantation 4 13 Living donor kidney transplantation 3 10 Other conditions, specified by responders a 11 35 Abbreviations: n, number. a Other reasons for selective antithrombotic prophylaxis: adolescent patients immobilized >2-3 days after kidney transplantation; recipients with a body weight <30 kg; recipients with polyuria; congenital thrombophilia; prothrombotic immunological disease; history of thrombosis of at least 2 vessels; recipients receiving already prophylactic or therapeutic anticoagulant therapy; intraoperative complications with high risk of thrombosis (n = 2); kidney transplant surgeon-and/or multi-professional decisions (n = 2).

| Timing of aP
Antithrombotic prophylaxis was started preoperatively in 11% The time-point for changing the drug to maintenance prophylaxis in centers using two drugs sequentially was on average 10 ± 6 days following pediatric KTx (29/35; 6 centers did not specify  Information S7. ASS-based aP strategies were conducted significantly longer than UFH-or LMWH-based strategies (127 ± 111 days vs 52 ± 78 days, respectively; P < .001). Detailed information for aP duration is provided in Table 4.  In centers practicing a management strategy with a change to another maintenance antithrombotic drug, most centers switchover within one to two weeks following pediatric KTx. 9,24 We assume that the selection of this time period correlates positively with the clinical improvement of the renal transplant patient, the associated renal transplant function, and lastly with the discharge from the hospital.

| D ISCUSS I ON
The considerable high multitude of antithrombotic management strategies represents uncertainty to the best practice which might arise from the limited evidence from few predominantly retrospective studies with small sample sizes. [10][11][12]15 In addition, there is only moderate to low quality evidence that anticoagulants are superior in prevention of venous thromboses and antiplatelets in arterial thromboses. 25,26 Notwithstanding, the favored antithrombotic drug is heparin in accordance with published studies in pediatric and adult KTx. 10,11,21 The preference for the anticoagulant heparin compared to the antiplatelet ASS may be traced back to short-term pharmacokinetic effects, the availability of an antidote, and therefore the lower attributed risk of clinical significant bleeding complications. 11,12 There is also a time-dependent preference toward the initial use of intravenous UFH compared to the subcutaneous application which might be explained by the already existing (central)

F I G U R E 4
Discontinuation of antithrombotic prophylaxis. Abbreviations: KTx, kidney transplantation; n, number venous lines and the assigned lower associated costs of UFH. 9,27 Notwithstanding, LMWH subcutaneously is the most often used overall antithrombotic drug, followed by UFH intravenously and oral ASS. [10][11][12]21 It remains uncertain if anticoagulation with heparin or antiplatelet management with ASS is superior in prevention of RGT. 5,9,18 There are a number of studies which suggest that the use of ASS decreases significantly the risk of RGT compared to heparin; however, the quality and reliability of the data needs to be determined. 5,18 For this reason, it is not surprising that oral ASS is the drug of choice for maintenance prophylaxis in these transplant centers which use two drugs sequentially for aP. 22 However, the convenient mode of oral application of ASS may play a more determining role in the decision-making process than the suggested higher effect of an antiplatelet management strategy compared to heparin. Of note, even though the alteration from heparin to oral ASS adds up from the clinical point of view, there is only one study showing a beneficial effect. 28 The evidence for combination of different drugs for aP is scarce and inconclusive. 15 Therefore, it is not a surprise that the simultaneous use of two drugs for aP was reported only as an alternative option for specific individual patients.
Interestingly, the information about dosing of the single drugs for aP was not only very limited due to an insufficient response rate but also highly heterogeneous which precludes a conclusive analysis. This finding is somewhat unclear as there are existing dosing recommendations and available blood parameters to monitor the effects of aP. 29,30 In addition, drug monitoring for aP was part of the management strategy in only slightly more than half of the transplant centers which is an inscrutable finding because thereby a critical evaluation of a dose-response correlation is not possible. 31   These studies, preferably prospective randomized controlled trials, are essential to further evaluate the benefits and risks of aP in pediatric KTx.