Pathophysiological Changes in the Hemostatic System and Antithrombotic Management in Kidney Transplant Recipients.

Nowadays, the main cause for early graft loss is renal graft thrombosis because kidney transplant outcomes have improved drastically owing to advances in immunological techniques and immunosuppression. However, data regarding the efficacy of antithrombotic therapy in the prevention of renal graft thrombosis are scarce. Adequate antithrombotic management requires a good understanding of the pathophysiological changes in the hemostatic system in patients with end-stage kidney disease (ESKD). Specifically, ESKD and dialysis disrupt the fine balance between pro- and anticoagulation in the body, and further changes in the hemostatic system occur during kidney transplantation. Consequently, kidney transplant recipients paradoxically are at risk for both thrombosis and bleeding. This overview focuses on the pathophysiological changes in hemostasis in ESKD and kidney transplantation and provides a comprehensive summary of the current evidence for antithrombotic management in (adult) kidney transplant recipients.

Antithrombotic Management in Adult Kidney Transplantation: A European Survey Study.

In kidney transplantation (KTx), renal graft thrombosis (RGT) is one of the main reasons for early graft loss. Although evidence-based guidance on prevention of RGT is lacking, thromboprophylaxis is widely used. The aim of this survey was to obtain a European view of the different thromboprophylactic strategies applied in KTx. An online 22-question survey, addressed to KTx professionals, was distributed by email and via platforms of the European Society for Organ Transplantation. Seventy-five responses (21 countries, 51 centers) were received: 75% had over 10 years' clinical experience, 64% were surgeons, 29% nephrologists, and 4% urologists. A written antithrombotic management protocol was available in 75% of centers. In 8 (16%) centers, respondents contradicted each other regarding the availability of a written protocol. Thromboprophylaxis is preferred by 78% of respondents, independent of existing antithrombotic management protocols. Ninety-two percent of respondents indicated that an anticipated bleeding risk is the main reason to discontinue chronic antithrombotic therapy preoperatively. Intraoperatively, 32% of respondents administer unfractionated heparin (400-10,000 international units with a median of 5,000) in selected cases. Despite an overall preference for perioperative thromboprophylaxis in KTx, there is a high variation within Europe regarding type, timing, and dosage, most likely due to the paucity of high-quality studies. Further research is warranted in order to develop better guidelines.

Aggravation of fibrin deposition and microthrombus formation within the graft during kidney transplantation.

In kidney transplantation, microthrombi and fibrin deposition may lead to local perfusion disorders and subsequently poor initial graft function. Microthrombi are often regarded as donor-derived. However, the incidence, time of development, and potential difference between living donor kidneys (LDK) and deceased donor kidneys(DDK), remains unclear. Two open-needle biopsies, taken at preimplantation and after reperfusion, were obtained from 17 LDK and 28 DDK transplanted between 2005 and 2008. Paraffin-embedded sections were immunohistochemically stained with anti-fibrinogen antibody. Fibrin deposition intensity in peritubular capillaries(PTC) and glomeruli was categorized as negative, weak, moderate or strong and the number of microthrombi/mm2 was quantified. Reperfusion biopsies showed more fibrin deposition (20% to 100% moderate/strong, p < 0.001) and more microthrombi/mm2 (0.97 ± 1.12 vs. 0.28 ± 0.53, p < 0.01) than preimplantation biopsies. In addition, more microthrombi/mm2 (0.38 ± 0.61 vs. 0.09 ± 0.22, p = 0.02) and stronger fibrin intensity in glomeruli (28% vs. 0%, p < 0.01) and PTC (14% vs. 0%, p = 0.02) were observed in preimplantation DDK than LDK biopsies. After reperfusion, microthrombi/mm2 were comparable (p = 0.23) for LDK (0.09 ± 0.22 to 0.76 ± 0.49, p = 0.03) and DDK (0.38 ± 0.61 to 0.90 ± 1.11, p = 0.07). Upon reperfusion, there is an aggravation of microthrombus formation and fibrin deposition within the graft. The prominent increase of microthrombi in LDK indicates that they are not merely donor-derived.

Gender Disparities in Authorships and Citations in Transplantation Research.

BACKGROUND: Over the past decades, there has been a rapid change in the gender ratio of medical doctors, whereas gender differences in academia remain apparent. In transplantation research, a field already understaffed with female doctors and researchers, there is little published data on the development in proportion, citations, and funding of female researchers over the past years. METHODS: To evaluate the academic impact of female doctors in transplantation research, we conducted a bibliometric analysis (01 January 1999 to 31 December 2018) of high-impact scientific publications, subsequent citations, and funding in this field. Web of Science data was used in combination with software R-Package "Gender," to predict gender by first names. RESULTS: For this study, 15 498 (36.2% female; 63.8% male) first and 13 345 (30.2% female; 69.8% male) last author gender matches were identified. An increase in the percentage of female first and last authors is seen in the period 1999-2018, with clear differences between countries (55.1% female authors in The Netherlands versus 13.1% in Japan, for example). When stratifying publications based on the number of citations, a decline was seen in the percentage of female authors, from 34.6%-30.7% in the first group (≤10 citations) to 20.8%-23.2% in the fifth group (>200 citations), for first (P < 0.001) and last (P = 0.014) authors, respectively. From all first author name-gender matches, 6574 (41.6% female; 58.4% male, P < 0.001) publications reported external funding, with 823 (35.5% female; 64.5% male, P = 0.701) reported funding by pharmaceutical companies and 1266 (36.6% female; 63.4% male, P < 0.001) reporting funding by the National Institutes of Health. CONCLUSIONS: This is the first analysis of gender bias in scientific publications, subsequent citations, and funding in transplantation research. We show ongoing differences between male and female authors in citation rates and rewarded funding in this field. This requires an active approach to increase female representation in research reporting and funding rewarding.

Kidney temperature during living donor kidney transplantation is associated with short-term measured glomerular filtration rate - a prospective study.

The duration of warm ischaemia time is associated with short- and long-term kidney transplant function. A quick rise in graft temperature is reported during the vascular anastomosis. This study was initiated to gain insight into the effect of graft temperature on short-term transplant function. From 2013 to 2015, data of living donor kidney transplant recipients were prospectively collected. At set intraoperative time points, the graft temperature was measured using a noncontact infrared thermometer. Primary endpoint was measured glomerular filtration rate (mGFR) at 3- and 6-month post-transplantation. Univariable and multivariable associations were identified using linear regression analyses. Multivariable analysis included models with donor, recipient and procedure characteristics. We evaluated 152 patients, 83 (55%) were male, mean ±SD age was 50.3 ± 13.4 years, and 79 (52%) were pre-emptively transplanted. In univariable analysis graft temperature, after 10 min of warm ischaemia was significantly associated with 3- and 6-month mGFR, ß -0.22 (95% CI -0.39 to -0.04, P = 0.01) and ß-0.22 (95% CI: -0.44 to -0.01, P = 0.04). The association remained significant in multivariable models. An independent association between kidney graft temperature and 3- and 6-month mGFR was identified. This association opens up the opportunity to further investigate the clinical impact of kidney rewarming during transplantation.

Perioperative antithrombotic therapy does not increase the incidence of early postoperative thromboembolic complications and bleeding in kidney transplantation - a retrospective study.

Perioperative antithrombotic therapy could play a role in preventing thromboembolic complications (TEC) after kidney transplantation (KTx), but little is known on postoperative bleeding risks. This retrospective analysis comprises 2000 single-organ KTx recipients transplanted between 2011 and 2016 in the two largest transplant centers of the Netherlands. TEC and bleeding events were scored ≤7 days post-KTx. Primary analyses were for associations of antithrombotic therapy with incidence of TEC and bleeding. Secondary analyses were for associations of other potential risk factors. Mean age was 55 ± 14 years, 59% was male and 60% received a living donor kidney. Twenty-one patients (1.1%) had a TEC. Multiple donor arteries [OR 2.79 (1.15-6.79)] and obesity [OR 2.85 (1.19-6.82)] were identified as potential risk factors for TEC. Bleeding occurred in 88 patients (4.4%) and incidence varied significantly between different antithrombotic therapies (P = 0.006). Cardiovascular disease [OR 2.01 (1.18-3.42)], pre-emptive KTx [OR 2.23 (1.28-3.89)], postoperative heparin infusion [OR 1.69 (1.00-2.85)], and vitamin K antagonists [OR 6.60 (2.95-14.77)] were associated with an increased bleeding risk. Intraoperative heparin and antiplatelet therapy were not associated with increased bleeding risk. These regimens appear to be safe for the possible prevention of TEC without increasing the risk for bleeding after KTx.

Preemptively and non-preemptively transplanted patients show a comparable hypercoagulable state prior to kidney transplantation compared to living kidney donors.

To prevent renal graft thrombosis in kidney transplantation, centres use different perioperative anticoagulant strategies, based on various risk factors. In our centre, patients transplanted preemptively are considered at increased risk of renal graft thrombosis compared to patients who are dialysis-dependent at time of transplantation. Therefore these patients are given a single dose of 5000 IU unfractionated heparin intraoperatively before clamping of the vessels. We questioned whether there is a difference in haemostatic state between preemptively and non-preemptively transplanted patients and whether the distinction in intraoperative heparin administration used in our center is justified. For this analysis, citrate samples of patients participating in the VAPOR-1 trial were used and several haemostatic and fibrinolytic parameters were measured in 29 preemptively and 28 non-preemptively transplanted patients and compared to 37 living kidney donors. Sample points were: induction anaesthesia (T1), 5 minutes after reperfusion (T2) and 2 hours postoperative (T3). At T1, recipient groups showed comparable elevated levels of platelet factor 4 (PF4, indicating platelet activation), prothrombin fragment F1+2 and D-dimer (indicating coagulation activation) and Von Willebrand Factor (indicating endothelial activation) compared to the donors. The Clot Lysis Time (CLT, a measure of fibrinolytic potential) was prolonged in both recipient groups compared to the donors. At T3, F1+2, PF4 and CLT were higher in non-preemptively transplanted recipients compared to preemptively transplanted recipients. Compared to donors, non-preemptive recipients showed a prolonged CLT, but comparable levels of PF4 and D-dimer. In conclusion pre-transplantation, preemptively and non-preemptively transplanted patients show a comparable enhanced haemostatic state. A distinction in intraoperative heparin administration between preemptive and non-preemptive transplantation does not seem justified.