Background: Uraemic platelet dysfunction is not completely understood, in part due to non-physiological platelet function assays. We have developed a physiological ﬂow-based assay that quantiﬁes platelet function in microlitre volumes of blood under arterial shear. The aim of this study was to characterize platelet function before and after kidney transplantation. Methods: Ten patients scheduled for living donor kidney transplant surgery and nine healthy controls were analysed using the assay. The motional parameters of platelet behaviour on von Willebrand factor (VWF) were recorded using customized platelet tracking software. The assay was repeated 3–8 weeks post-transplant in the transplant group and at an interval of>3 weeks in normal healthy volunteers. Results: Platelet–VWF interactions were markedly reduced in the 10 pre-transplant patients compared with the healthy controls. In seven patients with immediate graft function, dynamic platelet function returned to normal (despite a small decrease in haemoglobin and haematocrit), but remained markedly abnormal in the three patients with delayed graft function (DGF). Conclusions: Dynamic platelet function returned to normal following transplantation in those with immediate graft function. This early improvement was not observed in those with DGF. There may be important clinical implications, as patients with DGF are more likely to undergo invasive procedures, including transplant biopsies and insertion of central venous catheters. Key words: chronic kidney disease, delayed graft function, haemostasis, platelets, transplant Introduction antiplatelet/anticoagulant agents are often indicated and heparin End-stage renal disease (ESRD) is associated with an increased is administered during haemodialysis (HD) to avoid extracorpor- risk of bleeding, which manifests largely as bleeding into the skin eal clot formation . Certain anatomical abnormalities predis- and from mucosal surfaces . Medications contribute to this, as pose to bleeding, such as the presence of uraemic gastropathy . Received: September 19, 2017. Editorial decision: November 27, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/574/4816149 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Platelet function after kidney transplantation | 575 Platelet dysfunction also contributes to this increased bleeding been validated experimentally [21, 22]. We have also validated risk . the assay clinically: we previously demonstrated the capability When healthy endothelium is disrupted and the subendo- of this system to detect subtle changes in platelet function by thelial matrix is exposed, von Willebrand factor (VWF) binds to describing age-related changes in platelet behaviour, differen- the exposed surface and a coordinated series of events is set in ces between term and preterm neonates and changes in platelet motion to seal the defect. Under arterial shear conditions, plate- function between healthy pregnant and non-pregnant controls lets are tethered onto the immobilized VWF through the platelet [23–25]. glycoprotein (GP) Ib receptor and roll (translocate) along the sur- The aims of this study were to assess dynamic platelet func- face of the injured vessel wall. The initial tethering also initiates tion in patients with ESRD and to investigate the effect of renal a signalling cascade, which activates the GPIIb/IIIa receptor to transplantation on platelet function using the Dynamic Platelet bind VWF with high affinity, leading to platelet adhesion and Function Assay (DPFA). thrombus formation through cross-linking with fibrinogen at the site of injury. Materials and methods The platelet dysfunction seen in ESRD, termed uraemic pla- telet dysfunction, is multifactorial. GPIIb/IIIa is dysfunctional in Trial design ESRD . There is also abnormal GP expression, leading to hypo- Ethical approval was obtained from the Medical Research Ethics responsive platelets . Other factors include disrupted platelet Committee of Beaumont Hospital and the Royal College of granule release, depressed prostaglandin metabolism and abnormal platelet cytoskeletal assembly . Surgeons in Ireland. All data and samples were collected in accordance with the Declaration of Helsinki. Abnormal extrinsic factors also play a role, as evidenced by improved platelet function when uraemic platelets are mixed with normal plasma and unimproved function when normal Recruitment platelets are mixed with uraemic plasma . Although the cul- Consecutive adults (18 years old) scheduled for living donor prit toxins are not completely defined, guanidinosuccinic acid kidney transplant surgery were recruited. Patients were excluded and methylguanidine, which cause increased nitric oxide pro- if they were taking regular antiplatelet medication, regular anti- duction leading to impaired platelet aggregation, are likely key coagulation medication or had a platelet count<125 000/mL pre- players . Anaemia, common in ESRD, contributes to platelet transplant. Written informed consent was obtained and a dysfunction primarily due to rheologic factors . numerical trial identifier was assigned. Baseline demographics The end result of the above intrinsic and extrinsic factors is and laboratory results were recorded. dysfunctional platelet aggregation and platelet–endothelial Delayed graft function (DGF) was defined as the need for interactions. This has been demonstrated in patients with ESRD dialysis during the first week post-transplantation. A repeat using platelet aggregation assays in response to different ago- nists, adenosine diphosphate (ADP), epinephrine, thrombin and sample and updated clinical details were obtained at 3–8 weeks post-transplantation. Of note, one patient was taking aspirin at collagen [9, 10]. Successful kidney transplantation reverses the metabolic the time of the follow-up sampling. This was discontinued disarray of ESRD and is therefore likely to completely or parti- shortly afterwards and a third sample was analysed 4 weeks ally correct uraemic platelet dysfunction, although published later. reports are conflicting. Some platelet agonist studies have dem- Healthy controls were eligible for recruitment if they self- onstrated improved platelet aggregation post-transplant with reported as healthy and were not taking regular antiplatelet some, but not all, agonists [11–13]. Other groups did not demon- medication. They were excluded if they had consumed non- strate increased platelet aggregation with ADP, epinephrine, ris- steroidal anti-inflammatory medication in the preceding 2 tocetin or collagen [14–16]. weeks. A blood sample was obtained at baseline and at follow- However, platelet function studies should replicate the up (at least 3 weeks later). in vivo environment with flow and shear. Standard platelet function tests, performed in a research capacity, typically meas- Preparation of blood samples ure a single response to a single agonist and are not performed Venous blood was collected from the antecubital vein using a under arterial shear. Therefore they tend not to accurately cap- 20-gauge butterfly needle connected to a citrated Sarstedt ture the pathophysiological environment of complex disease monovette syringe (Drinagh, Wexford, Ireland). Blood samples states or the in vivo environment with flow and shear. Members of our research team developed the functional were kept at room temperature with gentle rocking and used assay utilized in this study over a number of years . It is a within 1 h of phlebotomy. Whole blood cell counts were microfluidic parallel-plate flow chamber coated with immobi- recorded for each donor, using a pocH-100i Haematology Analy- lized VWF, with a 0.1 mm cross-sectional area that provides ser (Sysmex Corporation, Kobe, Japan). uniform, well-defined shear rates (1500/s). Customized image processing quantifies dynamic cellular surface coverage versus DPFA time throughout the whole-blood flow assay for a given disease DPFA was performed as previously described . Briefly, cus- state. Outputs from the device and linked software include tom parallel-plate perfusion chambers were coated overnight instantaneous and mean platelet velocities, periods of motion with 100 lg/mL VWF, washed with phosphate-buffered saline and stasis and bond dissociation kinetics. It therefore has the and blocked with 1% bovine serum albumin for 1 h prior to use. capacity to detect subtle changes in platelet behaviour and pro- Whole blood was labelled with 1 mM3,3 -dihexyloxacarbocyanine vides detailed, reliable information regarding platelet function in an environment that replicates the in vivo environment. iodide for 5 min at 37 C prior to perfusion through the chamber This assay has been peer reviewed [17–20]. The accuracy of at an arterial rate of shear (1500/s). Platelet translocation behav- the outputs generated by the platelet tracking software has iour was recorded using real-time video microscopy at a frame Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/574/4816149 by Ed 'DeepDyve' Gillespie user on 07 August 2018 576 | C. Kennedy et al. rate of 19 frames/s. Image stacks were analysed by a custom (translocating platelets, translocation distance) and adherence designed and validated software package . to VWF (adhesion rate, percentage of platelet surface coverage). The assay measurements obtained from this analysis meas- ure the following aspects of dynamic platelet behaviour: tether- Statistical methods ing to the VWF surface (platelet tracks), rolling across VWF The mean and standard deviation were determined for each measured parameter. The distribution of each measured Table 1. Baseline demographics in transplant candidates and parameter was determined by Shapiro–Wilk test to inform the healthy controls choice of a parametric (independent samples t-test) or non- parametric test (Mann–Whitney test) when comparing groups. Transplant Healthy Paired t-tests were used to compare individual measurements Demographics candidates controls within groups. Values were considered statistically significant Age (years), mean (range) 40.5 (28–54) 43.6 (28–64) at P < 0.05. Gender (male), % 50 44 Hierarchical cluster analysis using Ward’s linkage analysis Cause of ESRD, n NA (Euclidean distance) was used to determine similarity between the IgA nephropathy 5 transplant recipients, using the difference in pre- and post- SLE 1 transplantation values as input. Spearman and Pearson correlation Alport syndrome 1 analysis was carried out on these parameters and significantly cor- ADPKD 1 related variables were not included in the cluster analysis. FSGS 1 RRT, n NA Pre-emptive 2 Results Haemodialysis 6 Clinical characteristics Peritoneal dialysis 2 Dialysis vintage (months), mean (range) 11 (0–30) NA Ten patients and nine healthy controls were recruited over a 2- Medications, n 0 year period (Table 1). One patient had lupus with normal plate- Mean (range) 5.5 (0–11) let count pre-transplant (235 000/mL). Taking ESA 5 All 10 patients underwent living donor kidney transplanta- Current smokers, n 00 tion, with basiliximab (n ¼ 9) or anti-thymocyte globulin (n ¼ 1) induction therapy. Maintenance immunosuppression was IgA, immunoglobulin A; SLE, systemic lupus erythematosus; ADPKD, autosomal tacrolimus, mycophenolate mofetil and prednisolone for all dominant polycystic kidney disease; FSGS, focal segmental glomerular sclerosis; patients. Although three patients had DGF initially, all had inde- RRT, renal replacement therapy; ESA, erythropoiesis-stimulating agent. pendent transplant function (serum creatinine 91–248 mmol/L) at the time of follow-up analysis (Table 2). Table 2. Laboratory results [mean (range)] on the day of platelet analysis pre- and post-transplant Platelet function In the control group, platelet function was normal at baseline Laboratory results Pre-transplant Post-transplant and did not significantly change at follow-up. Measures of pla- Haemoglobin (g/dL) 12.4 (10.9–14.6)** 10.4 (6.6–12.7)** telet tethering, rolling and adhesion were reduced in the pre- White cell count ( 10 /L) 7.5 (3.2–9.9) 7.8 (4.2–12.6) transplant group at baseline (Table 3, Figure 1). Platelet count ( 10 /mL) 248 (201–346)** 284 (242–339)** Seven transplant recipients had a statistically significant INR 1.02 (0.96–1.12) 1.02 (0.93–1.09) improvement in post-transplant dynamic platelet function APTT (s) 27.8 (22.8–35.1) 30.5 (25.5–35) despite a small drop in mean haemoglobin and haematocrit Creatinine (mmol/L) 668.3 (278–1024)** 155.2 (91–248)** (which one would expect to lead to reduced platelet–endothelial Urea (mmol/L) 18.1 (11.9–25.1)** 8.36 (4.2–11.3)** interactions) (Tables 2 and 3, Figure 2). All of these patients had excellent immediate transplant function. INR, international normalized ratio; APTT, activated partial thromboplastin time. Platelet interactions did not improve in three transplant **P< 0.05. recipients (Table 3, Figure 2). Unbiased cluster analysis of the 10 Table 3. Patients with advanced chronic kidney disease have signiﬁcantly reduced platelet tethering compared with healthy controls Healthy controls Pre-transplant Immediate graft Parameter (n ¼ 9) (n ¼ 10) function (n ¼ 7) DGF (n ¼ 3) Platelet tethering 8066 289** 5386 246** 8396 348 4916 122 tracks (n) Platelet rolling Translocation distance (mm) 10.26 2.8 12.26 4.4 13.36 5.4 10.96 3.4 Translocating platelets (n) 5056 182 3726 198 5916 295 3326 50 Platelet adhesion Adhesion rate 0.456 0.07 0.396 0.09 0.466 0.08 0.396 0.07 Platelet surface coverage (%) 14.16 1.5 12.26 2.7 13.96 1.6 12.06 1.1 Dynamic platelet function returns to normal following successful transplantation. **P< 0.05. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/574/4816149 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Platelet function after kidney transplantation | 577 post-transplant samples identified the same three patient out- had post-transplant DGF. One patient with DGF (KTX10) was liers in terms of dynamic platelet function—KTX04, KTX06 also started on aspirin prior to the follow-up sample (see sec- and KTX10 (Figure 2). The three outliers had similar baseline tions ‘Materials and methods’ and ‘Serial testing’). clinical characteristics to the remaining patients, but all three Serial testing Serial samples were obtained from two of three outliers with a view to better understand platelet function over time. The patient KTX04 was lost to follow-up. KTX06 had a third sample taken on the second anniversary of the transplant surgery. The transplant function was excellent with a creatinine of 78 mmol/L. The parameters of platelet func- tion had normalized and, when compared with the initial results, were no longer different from those patients with nor- mal function post-transplant (Figures 3 and 4). KTX10 had a creatinine of 248 mmol/L, haemoglobin of 6.6 g/dL (following a bleed) and was taking aspirin at the time of the follow-up sample. Aspirin was discontinued a few days later. A third sample was analysed 6 weeks after aspirin discontinuation, by which time the haemoglobin had significantly improved (10.1 g/dL) and transplant function was slowly recovering (creati- nine 183 mmol/L). Platelet function in the third post-transplant sample was similar to that in the second. Discussion Fig. 1. Platelet tethering (tracks) is signiﬁcantly reduced in those with advanced The results of the present study demonstrate, for the first time, chronic kidney disease compared with healthy controls; platelet rolling (translocat- reduced platelet–VWF interactions in patients with ESRD await- ing platelets) is also reduced in those pre-transplant (P¼ 0.0470 and 0.1468, respec- tively). Platelet tethering (tracks) and rolling (translocating platelets) normalize in ing transplant using a physiological flow-based assay. Successful those with immediate graft function but remain abnormal in those with DGF. kidney transplantation normalized these interactions. This early Fig. 2. A hierarchical cluster analysis using Ward’s linkage analysis. The ﬁgure reads from right to left; two groups quickly separate in terms of similarity for dynamic platelet function. The three outliers, in terms of dynamic platelet function, are patients KTX04, KTX06 and KTX10, all of whom had DGF. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/574/4816149 by Ed 'DeepDyve' Gillespie user on 07 August 2018 578 | C. Kennedy et al. Fig. 3. A scatter plot of two parameters of dynamic platelet function (number of translocating platelets versus adhesion rate) for the 10 transplant recipients. A single value was obtained for each patient by subtracting their post-transplant assay result from their pre-transplant assay result. The scatter plot identiﬁed Fig. 4. A scatter plot of two parameters of dynamic platelet function (number of three outlying patients, all of whom had DGF, with no improvement in platelet translocating platelets versus adhesion rate) for the 10 transplant recipients. function post-transplant (represented by the squares in the lower portion of the Again, a single value was obtained for patients by subtracting their post-trans- plot). The circles in the upper portion of the plot represent the seven patients plant assay result from their pre-transplant assay result. The circles represent with immediate graft function who demonstrated an improvement in platelet those with immediate graft function who demonstrated an improvement in pla- function. telet function. Of the three outliers with DGF and persistently abnormal platelet function post-transplant (squares), one had repeat testing 2 years later and demonstrated an improved platelet proﬁle (triangle). Creatinine Age at follow-up levels by Days 30–60 and 45–60, respectively. Those 29 patients Patient Gender (years) Cause of ESRD DGF (mmol/L) with DGF had significant differences from the remaining patients during the early days post-transplant; platelet count was lower, 1 Female 50 Focal segmental No 121 while MPV, P-LCR and platelet volume distribution width were glomerulosclerosis higher . 2 Male 34 Polycystic kidney disease No 174 Our results suggest that meticulous attention to haemosta- 3 Female 54 IgA nephropathy No 125 sis must be given for a considerable time post-transplant in 4 Female 30 IgA nephropathy Yes 111 those with DGF, which is usually related to ischaemic injury 5 Male 28 IgA nephropathy No 213 6 Female 37 IgA nephropathy Yes 79 and, as with any acute kidney injury, takes a variable duration 7 Male 49 Unknown No 173 time for recovery. Nephrologists generally pay close attention to 8 Male 38 IgA nephropathy No 217 haemostasis in patients on dialysis undergoing invasive 9 Female 54 Lupus nephritis No 91 procedures, with a focus on pre-procedure dialysis, administra- 10 Male 31 Alport syndrome Yes 248 tion of desmopressin and correction of anaemia with erythro- poietin/iron. We suggest that similar caution be taken in IgA, immunoglobulin A. patients with DGF in the post-transplant setting. Indeed, those with DGF require more frequent invasive procedures such as improvement was not observed in the three patients who biopsies and central venous catheter insertion. It was interest- had DGF. ing to note that KTX10 had a clinically significant bleed follow- We postulated that results may have been skewed some- ing a transplant biopsy several days prior to the second platelet what by KTX10, who was an extreme outlier in many ways and assay. taking aspirin at the time of post-transplant assay. It is known It is noteworthy that the role of aspirin, which inhibits plate- that patients with ESRD can display increased bleeding sensitiv- let aggregation via cyclooxygenase-mediated prostaglandin pro- ity to aspirin compared with healthy controls . However, duction, has not been entirely clarified in the post-transplant when repeated 4 weeks later when some of the confounding setting. It is continued post-transplant as secondary prevention issues had been resolved (and transplant function was still in in patients with clinically significant cardiovascular disease. It the recovery phase), platelet function looked to be similar. is generally accepted (but not universally enforced) that if there Serial sampling of KTX06 demonstrated improvement of plate- is a clear indication for primary prevention with aspirin, it will let function over time in the setting of excellent graft function. be given post-transplant . There is controversy regarding Another research group reported a difference in various aspirin administration to all post-transplant recipients, irre- platelet parameters in those with DGF post-transplant, spective of their cardiovascular risk profile [29, 30]. It is likely although this was a retrospective review of laboratory data. In that in the future a more personalized approach to anti-platelet 232 transplant recipients, a decrease in platelet number and therapy will be developed, in which graft function and meas- platelet haematocrit was noted in the first 5 days post- ures of dynamic platelet function are considered. transplant, followed by recovery in Days 30–60. Mean platelet vol- We conclude that platelet–VWF interactions are markedly ume (MPV) and large platelet ratio (P-LCR) slowly rose from Day abnormal in patients with ESRD. Excellent, immediate trans- 15 onwards and were significantly higher than pre-transplant plant function is associated with normalized platelet function Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/574/4816149 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Platelet function after kidney transplantation | 579 exposure of ﬁbrinogen receptors by adenosine diphosphate within weeks of the surgery. DGF is associated with persistence or collagen. J Lab Clin Med 1986; 108: 246–252 of the abnormalities, but the results for KTX06 suggest this may improve in the longer term in line with renal recovery. This 11. Sahin G, Temiz G, Ozkurt S et al.Effectoftransplantonplatelet function markers (p-selectin and platelet aggregation) and adi- research was hypothesis generating; we now plan to study the ponectin in renal transplant patients. Exp Clin Transplant 2016; hypothesis that platelet function improves in association with doi: 10.6002/ect.2016.0105 renal recovery following transplant surgery by testing serial 12. Cesari F, Marcucci R, Gori AM et al. High platelet turnover samples in a cohort of transplant recipients. and reactivity in renal transplant recipients patients. Thromb Haemost 2010; 104: 804–810 Authors’ contributions 13. Zanazzi M, Cesari F, Rosso G et al. Reticulated platelets and platelet reactivity in renal transplant recipients receiving C.K. was responsible for study design, acquisition and interpre- antiplatelet therapy. Transplant Proc 2010; 42: 1156–1157 tation of data and drafting and revising the manuscript. L.W. 14. Sahin G, Akay OM, Uslu S et al. Association between endothe- was responsible for study conception and design, acquisition lial and platelet function markers and adiponectin in renal and interpretation of data and critical review of the manuscript. transplanted recipients on cyclosporine and tacrolimus immu- D.S. was responsible for acquisition of data and critical review nosuppression based therapy. Nephrology 2015; 20: 392–398 of the manuscript. J.C. was responsible for study conception 15. Sahin G, Akay OM, Bal C et al. The effect of calcineurin inhibi- and design, analysis and interpretation of data and critical tors on endothelial and platelet function in renal transplant review of the manuscript. I.O. and M.K. were responsible for patients. Clin Nephrol 2011; 76: 218–225 analysis and interpretation of data and critical review of the 16. Sahin G, Akay OM, Kus E et al. Effects of immunosuppressive manuscript. 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Clinical Kidney Journal – Oxford University Press
Published: Aug 1, 2018
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