Efficacy and safety of low-dose aspirin on preventing transplant renal artery stenosis: a prospective randomized controlled trial

Abstract

Background: 

Transplant renal artery stenosis (TRAS) is a vascular complication after kidney transplantation associated with poor outcomes. This study aimed to analyze the efficacy and safety of low-dose aspirin for preventing TRAS.

Methods: 

After kidney transplantation, patients were enrolled from January 2018 to December 2020 in Henan Provincial People's Hospital. A total of 351 enrolled recipients were randomized to an aspirin group with low-dose intake of aspirin in addition to standard treatment (n = 178), or a control group with only standard treatment (n = 173). The patients was initially diagnosed as TRAS (id-TRAS) by Doppler ultrasound, and confirmed cases were diagnosed by DSA (c-TRAS).

Results: 

In the aspirin and control groups, 15.7% (28/178) and 22.0% (38/173) of the recipients developed id-TRAS, respectively, with no statistical difference. However, for c-TRAS, the difference of incidence and cumulative incidence was statistically significant. The incidence of c-TRAS was lower in the aspirin group compared with the control group (2.8% [5/178] vs. 11.6% [20/173], P = 0.001). Kaplan–Meier estimates and Cox regression model identified the cumulative incidence and hazard ratio (HR) of TRAS over time in two groups, showing that recipients treated with aspirin had a significantly lower risk of c-TRAS than those who were not treated (log-rank P = 0.001, HR = 0.23, 95% confidence interval [CI]: 0.09–0.62). The levels of platelet aggregation rate (P < 0.001), cholesterol (P = 0.028), and low-density lipoprotein cholesterol (P = 0.003) in the aspirin group were decreased compared with the control group in the third-month post-transplantation. For the incidence of adverse events, there was no statistical difference.

Conclusion: 

Clinical application of low-dose aspirin after renal transplant could prevent the development of TRAS without significant adverse effects.

Trial Registration: 

Clinicaltrials.gov, NCT04260828.

Introduction

Transplant renal artery stenosis (TRAS) is a well-recognized vascular complication following kidney transplantation characterized by resistant hypertension and damage to the transplanted renal hemodynamics and function.^[1,2] It usually occurs between 3 and 24 months after surgery, most frequently within 6 months. The reported incidence of TRAS from various centers ranged from 0.6% to 25%.^[1-8] Based on the time of onset, it could be classified as early onset (within 90 days) and later onset (after 90 days). The development of early onset TRAS was considered to be involved in trauma in vessels during surgical procedures such as capturing organs, suturing, attachment, and multivessel renal artery. The later onset may be associated with immunological damage, infection, atherosclerosis, and etc.^[9] TRAS was a critical cause of graft loss and even premature death in recipients, representing one of the great challenges for transplant clinicians.

Aspirin, an irreversible inhibitor of cyclooxygenase (COX)-1/-2, is widely used as an antipyretic, anti-inflammatory, analgesic, and antiplatelet aggregation agent. It irreversibly acetylates platelet COX-1 which inhibits the production of platelet-derived thromboxane A2 and, thereby, blocks platelet activation and aggregation that initiates blood clotting in damaged blood vessels.^[10,11] The application of aspirin in inhibiting thrombotic damage is well-established for the treatment of various cardiovascular diseases and their complications.^[12] In addition, aspirin exerts various protective effects on cardiocerebrovascular disease by mechanisms of anti-inflammatory, endothelium-protective, and anti-atherosclerotic properties beyond platelet inhibition.^[13-18] Detailed understanding of these mechanisms may make prophylactic treatment of aspirin for TRAS possible.

However, there are limited data on the use of low-dose aspirin for kidney transplantation recipients because of their low aspirin application rate.^[19] We conducted a retrospective study previously indicating that low-dose aspirin could reduce the incidence of TRAS.^[20] To further confirm it, we aimed to evaluate the efficacy and safety of aspirin for prophylaxis of TRAS in a randomized controlled trial (Clinicaltrials.gov, NCT04260828).

Methods

Ethical approval

All of the donations were voluntary. All participants provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was provided by the Clinical Research Ethics Committee of Henan Provincial People's Hospital (No. 2019132).

Participants

Eligible study participants aged ≥18 years were identified among recipients of kidney transplantation at Henan Provincial People's Hospital, a tertiary teaching hospital in Zhengzhou, China between January 1, 2018, and December 31, 2020. They underwent renal transplantation before enrollment and had allografts with stable renal function. They fulfilled the following inclusion criteria at the baseline evaluation: providing written informed consent; no history of adverse effects from aspirin; and stable on standard immunosuppressive treatment with tacrolimus, mycophenolate mofetil (MMF)/mycophenolate sodium (MPS), and prednisone. Exclusion criteria were donor age >70 years; allergy or intolerance to aspirin; usage of other non-steroidal anti-inflammatory drugs, anti-coagulants or antiplatelets; active gastrointestinal bleeding or history of severe peptic ulcer; severe bleeding tendency or severe liver disease; delayed graft function; severe rejection or graft loss after kidney transplantation within 3 months; cerebral hemorrhage or cerebral infarction within 3 months; severe thrombotic events; severe systemic infection; and participation in other clinical trials. Females of reproductive age were tested for pregnancy at the screening visit and were informed to avoid pregnancy during the study. Any type of non-steroidal anti-inflammatory drugs and anti-coagulants apart from the study medication was not allowed to use during the study. Of totally 372 patients undergoing renal transplantation performed by the same surgical team at our hospital, 368 patients were eligible for inclusion criteria and 351 patients were eventually included in the final analysis [Figure 1].

Figure 1: Flowchart of patient enrolment in the study of efficacy and safety of low-dose aspirin on preventing transplant renal artery stenosis.

Study design and interventions

This was an investigator-initiated, open-label, single-center, randomized prospective clinical trial. The trial was conducted for evaluating the benefits and risks of low-dose aspirin (Bayaspirin Enteric-coated Tablets; Bayer Health Care Manufacturing S.r.l, Italy) 100 mg daily in preventing TRAS among renal transplant recipients. The dose of 100 mg every day was chosen to be the effective dose while trying to minimize gastrointestinal side effects. Continuous administration of aspirin was started in the second week after successful renal transplantation in the experimental group, lasting for >3 months. Patients were instructed to take enteric-coated aspirin daily on an empty stomach to assure absorption, to reduce gastric irritation, and to avoid possible interference with other medication. The intervention in blank control group had no aspirin-taking. After post-transplantation enrollment, patients were randomly assigned to one of the aspirin groups or control groups at a 1:1 allocation ratio based on a computer-generated random number list.

Patients in both groups were treated with standard immunosuppressive protocol, including induction with anti-thymocyte globulin (Thymoglobuline; Genzyme-Sanofi, France), followed by maintenance immunosuppression with tacrolimus (Prograf; Astellas, Japan), MMF (CellCept; Roche, Switzerland)/MPS (Myfortic; Novartis, Germany), and prednisone (Zhejiang Xianju, China). The dosage of tacrolimus was weight-based (0.05 mg/kg twice daily) started at the time of transplantation and then adjusted according to close monitoring to maintain tacrolimus blood concentrations within the therapeutic range (6–8 ng/mL) to ensure efficacy and safety. We used MMF 750 mg twice daily or MPS 540 mg twice daily. One dose of methylprednisolone was given at the time of transplantation and 500, 300, 200, and 80 mg were given on post-operative days 1 to 4, respectively. Subsequently, the substitution of methylprednisolone by oral prednisone was started with the initial dose of 50 mg daily and then tapered down gradually to 10 mg daily as a maintenance dose.

Follow-up

Patients were followed up once a week for the first month after transplantation, once a month for the next 5 months, and every 2 months thereafter. Close contact was maintained between the patients and our center, and patients were to be additionally followed up immediately if any changes in their condition occurred. Measurements at each follow-up visit included Doppler ultrasound (DUS) of the transplanted renal arteries, routine blood tests, arachidonic acid-induced platelet aggregation rate assay, routine urinalysis, renal and liver function analysis, and blood lipid levels analysis. The choice of computed tomography angiography (CTA) exploration for suspicious TRAS patients depended on patients’ tolerability. Digital subtraction angiography (DSA) would be necessary when DUS with or without CTA showed stenosis of renal vessels with significant clinical symptoms.

Diagnosis of TRAS and treatment

We divided patients into two types of TRAS, initially diagnosed TRAS (id-TRAS) and confirmed TRAS (c-TRAS). The id-TRAS is defined as grafted renal artery stenosis that is asymptomatic or has mild controllable symptoms at routine screenings. DUS is the primary imaging tool in the initial screening and follow-up of TRAS due to its inexpensive and non-invasive characters. All the DUS examinations were performed by the same sonographer well trained and highly experienced in transplanted renal vascular ultrasound imaging. CTA can be used as a complementary tool of screening for patients with suspected TRAS by DUS who can receive ionizing radiation and intravenous contrast medium. Imaging features included transplanted renal artery DUS velocity acceleration (peak systolic velocity [PSV] >200 cm/s, the ratio of the PSV in the renal artery to that in interlobar artery >9.1),^[21] or CTA with evident stenosis >60% and/or post-stenotic dilation. Patients with id-TRAS were observed dynamically without further invasive examination and, if necessary, symptomatic treatment, such as control of hypertension by oral anti-hypertensive medication, were performed. Most of them can remain stable over time, or can even relieve spontaneously. The c-TRAS is defined as the stenosis of the grafted renal artery with clinical signs (such as refractory hypertension or progressive creatinine elevation or oliguria) after initial diagnosis by screenings and further confirmed by the gold standard DSA. Because DSA is invasive, expensive, and potentially risky to the transplanted kidney, rigorous screening is required. Percutaneous transluminal angioplasty (PTA) with or without stenting was used to treat c-TRAS. The calculation of renal artery stenosis rate conformed to NASCET standard is as follows: lumen stenosis rate = (normal diameter of the distal end of the stenosis-narrowest diameter of the stenotic segment)/(normal diameter of the distal end of the stenosis)×100%.^[22]

Primary and secondary endpoints

The primary endpoint was the incidence of TRAS, including id-TRAS and c-TRAS, the degree and location of stenosis in the renal artery, and the time from transplantation to the first occurrence of id-TRAS. Secondary endpoints were changes in parameters of renal function, blood cells, blood biochemical indexes, blood lipid levels, and C-reactive protein. From a safety point of view, the incidence of adverse clinical events was also evaluated.

Statistical analysis

Values were expressed as mean and standard deviation for continuous variables with normal distribution, median (interquartile range) for non-normally distributed variables, and number with percentage of the total for categorical variables. Intergroup comparisons of the patient's baseline characteristics and stenosis conditions were performed using Pearson's χ² tests or Mann–Whitney U tests. Cumulative event rates were calculated according to the Kaplan–Meier method for the primary endpoint of diagnosis of id-TRAS and c-TRAS and compared using the log-rank test. The hazard ratio (HR) was estimated by the Cox regression model with adjustment of age and sex. Intergroup comparison of the incidence of clinical adverse events was performed using Pearson's χ² tests, continuity correction χ² tests, or Fisher's exact test. A comparison of laboratory indicators in two groups was performed using Mann–Whitney U tests or independent-samples t-tests. All statistical analyses were performed using R version 3.6.0 (https://www.r-project.org/, R Foundation for Statistical Computing, Vienna, Austria). A two-sided P value of <0.05 was considered statistically significant.

The study sample size was calculated based on our previous retrospective analysis of the effect of aspirin on preventing TRAS among recipients with ischemic heart or cerebrovascular diseases. It was estimated that the prevalence of TRAS was 7.5% in the arm treated with aspirin and 17.6% in the arm without aspirin. For this trial to have a power of 80% with type I error (α) of 5% in a two-sided statistical model, the required sample size was 338 patients in total, with 169 patients in each treatment arm. Considering the possibility of loss to follow-up due to various factors, we appropriately increased recruitment numbers and the final sample size of the analysis was slightly higher than the estimated.

Results

Baseline characteristics

There was no significant difference between the aspirin group (n = 178) and control group (n = 173) in age, sex, primary disease, underlying diseases, infectious diseases, dialysis time, usage of immunosuppressive drugs, whether multiple renal arteries, allograft type, and whether statins were used (all P > 0.05). There was a significant statistical difference in the mode of renal artery anastomosis between the two groups (P = 0.002) [Table 1].

Table 1 - Baseline characteristics of the study patients kidney transplantation recipients in aspirin group and control group.

Characteristics	Aspirin group (n = 178)	Control group (n = 173)	Statistical values	P values
Age (years)	36.0 (30.0, 44.0)	36.0 (30.0, 44.0)	−0.184	0.855∗
Sex			0.071	0.790
Male	144 (80.9)	138 (79.8)
Female	34 (19.1)	35 (20.2)
Primary disease			1.025	0.961
Glomerulonephritis	55 (31.0)	53 (30.6)
Hypertensive nephropathy	12 (6.7)	9 (5.2)
Diabetic nephropathy	4 (2.2)	6 (3.5)
Polycystic kidney	3 (1.7)	4 (2.3)
Others	8 (4.5)	7 (4.1)
Unknown	96 (53.9)	94 (54.3)
Underlying diseases			0.126	0.939
Hypertension	152 (85.4)	150 (86.7)
Hypertension and diabetes	9 (5.1)	8 (4.6)
None	17 (9.5)	15 (8.7)
Infectious diseases			1.799	0.180
HBV/HCV/syphilis	9 (5.1)	15 (8.7)
None	169 (94.9)	158 (91.3)
Dialysis time (months)	12.0 (6.0, 25.5)	12.0 (7.0, 30.0)	−0.539	0.591∗
Immunosuppressive drugs			0.438	0.508
Tac + MMF + Pred	165 (92.7)	157 (90.8)
Tac + MPS + Pred	13 (7.3)	16 (9.2)
Number of arteries			0.207	0.649
Single	163 (91.6)	156 (90.2)
Double	15 (8.4)	17 (9.8)
Renal arterial anastomosis			12.780	0.002
Internal iliac artery	94 (52.8)	117 (67.6)
External iliac artery	76 (42.7)	43 (24.9)
Internal iliac artery and external iliac artery	8 (4.5)	13 (7.5)
Allograft type			2.016	0.156
Deceased	118 (66.3)	102 (59.0)
Living	60 (33.7)	71 (41.0)
Statins or not after transplantation			2.206	0.137
Yes	85 (47.8)	69 (39.9)
No	93 (52.2)	104 (60.1)

Baseline patient characteristics are presented as numbers (%) for categorical variables or median (the lower quartile, the upper quartile) for continuous variables.

^∗Refers to Mann–Whitney U test, and others were tested by Pearson χ² test.HBV: Hepatitis B virus; HCV: Hepatitis C virus; Tac: Tacrolimus; MMF: Mycophenolate mofetil; MPS: Mycophenolate sodium; Pred: Prednisone.

Comparison of TRAS incidence between groups

During a median follow-up of 17.6 months, 66/351 (18.8%) patients had developed id-TRAS, 28/178 (15.7%) in the aspirin group, and 38/173 (22.0%) in the control group. There was no significant difference in id-TRAS incidence, lumen stenosis rate, stenotic location, and duration from transplantation to id-TRAS (P > 0.05). All c-TRAS was progressed from id-TRAS. There were 25/351 (7.1%) recipients with c-TRAS, representing 37.9% (25/66) of all kinds of TRAS, including 5/178 (2.8%) patients in the aspirin group, and 20/173 (11.6%) patients in the control group. The incidences of c-TRAS between the two groups were significantly different (P = 0.001) [Table 2].

Table 2 - The occurrence of TRAS among the kidney transplantation recipients in aspirin group and control group.

Variables	Aspirin group (n = 178)	Control group (n = 173)	Statistical values	P values
id-TRAS	28 (15.7)	38 (22.0)	2.234	0.135
Lumen stenosis rate	56.0 (48.6, 68.4)	64.5 (47.1, 83.0)	−1.194	0.235∗
Stenotic location			1.663	0.197
Anastomosis	14 (50.0)	13 (34.2)
Proximal end of anastomosis	14 (50.0)	25 (65.8)
Duration from transplantation to TRAS (days)	105.5 (72.5, 155.5)	105.0 (72.2, 119.0)	−0.539	0.595∗
c-TRAS	5 (2.8)	20 (11.6)	10.158	0.001

Continuous variables are presented as median (the lower quartile, the upper quartile) and categorical variables as numbers (%).

^∗Refers to Mann-Whitney U test, and others were tested by Pearson χ² test.id-TRAS: Initially diagnosed TRAS; c-TRAS: Confirmed TRAS; TRAS: Transplant renal artery stenosis.

We analyzed the cumulative incidence of TRAS over time. The results showed that the cumulative incidence of id-TRAS in the aspirin group was 16.5% (95% confidence interval [CI]: 10.6%–22.0%) at 42 months, while that in the control group was 22.5% (95% CI: 15.9%–28.6%; log-rank P = 0.110; Figure 2A). The cumulative incidence of c-TRAS was 3% (95% CI: 0.4%–5.5%) in the aspirin group and was 12.5% in the control group (95% CI: 7.2%–17.5%; log-rank P = 0.001; Figure 2B). The Cox regression model 1 with adjustment of age and sex, and model 2 with adjustment of covariates including hypertension, diabetes, infectious diseases, dialysis time, immunosuppressive drugs, number of arteries, renal arterial anastomosis, allograft type, and statins treatment apart from age and sex were further used to calculate HR. Compared with the control group, the risk of id-TRAS decreased by 32% (HR: 0.68, 95% CI: 0.42–1.10; Figure 2A) and the risk of c-TRAS decreased by 77% (HR: 0.23, 95% CI: 0.09–0.62; Figure 2B). In the mode 2, the HR value of the risk of id-TRAS and c-TRAS further decreased. The subgroup analysis according to the mode of renal artery anastomosis showed that the HR value of different groups was similar to the total population [Table 3].

Figure 2: Kaplan-Meier curve for incidence of id-TRAS (A) and c-TRAS (B). CI: Confidence interval; HR: Hazard ratio; id-TRAS: Initially diagnosed TRAS; TRAS: Transplant renal artery stenosis; c-TRAS: Confirmed TRAS.

Table 3 - The effect of aspirin on TRAS incidence in different type of renal arterial anastomosis.

	id-TRAS		c-TRAS
Items	HR (95% CI)	P values	HR (95% CI)	P values
Total population
Model 1∗	0.68 (0.42–1.10)	0.118	0.23 (0.09–0.62)	0.003
Model 2†	0.59 (0.35–0.99)	0.047	0.20 (0.07–0.55)	0.002
Single artery
Model 1∗	0.67 (0.39–1.15)	0.147	0.23 (0.08–0.68)	0.008
Model 2†	0.60 (0.34–1.05)	0.073	0.21 (0.07–0.66)	0.007
Internal iliac artery
Model 1∗	0.58 (0.28–1.19)	0.135	0.20 (0.04–0.90)	0.036
Model 2†	0.47 (0.22–1.00)	0.051	0.20 (0.04–0.90)	0.036
External iliac artery
Model 1∗	0.77 (0.34–1.74)	0.532	0.35 (0.08–1.50)	0.158
Model 2†	0.55 (0.23–1.32)	0.181	0.13 (0.03–0.55)	0.006

^∗Model 1: HRs (95% CIs) were estimated from the Cox regression model with adjustment of age and sex.

^†Model 2: HRs (95% CIs) were estimated from the Cox regression model with adjustment of age, sex, hypertension, diabetes, infectious diseases, dialysis time, immunosuppressive drugs, number of arteries, renal arterial anastomosis, allograft type, and statins treatment.CI: Confidence interval; c-TRAS: Confirmed TRAS; HR: Hazard ratio; id-TRAS: Initially diagnosed TRAS; TRAS: Transplant renal artery stenosis.

Comparison of intervention

Of the 28 patients with id-TRAS in the aspirin group, 23 were kept under dynamic observation, and the other five progressed to c-TRAS confirmed by DSA, of which four were treated with balloon dilatation and one with stent implantation. Of the 38 patients with id-TRAS in the control group, 18 were kept under dynamic observation and the other 20 progressed to c-TRAS confirmed by DSA, of which 17 were treated with balloon dilatation and three with stent implantation. Satisfactory therapeutic effects were achieved.

Clinical adverse events

There was no significant difference in total clinical adverse events, hemorrhagic diseases, infarct diseases, and thrombotic diseases between the two groups (P > 0.05). The proportion of patients with hemorrhagic diseases in the aspirin group was slightly higher than that in the control group, and the proportion of patients with infarct diseases and thrombotic diseases in the experimental group was slightly lower than that in the control group, although with no significant difference between two groups. There was also no significant difference in graft failure and death between the two groups (P > 0.05) [Table 4].

Table 4 - Comparison of clinical adverse events among the kidney transplantation recipients between aspirin group and control group.

Adverse events	Aspirin group (n = 178)	Control group (n = 173)	Statistical values	P values
Total clinical adverse events	30 (16.9)	26 (15.0)	0.218	0.641∗
Hemorrhagic diseases	18 (10.1)	10 (5.8)	2.243	0.134∗
Severe peptic ulcer	7 (3.9)	3 (1.7)
Gastrointestinal bleeding	3 (1.7)	1 (0.6)
Conjunctival hemorrhage	3 (1.7)	1 (0.6)
Cerebral hemorrhage	2 (1.1)	1 (0.6)
Uterine bleeding	1 (0.6)	2 (1.2)
Urinary bleeding	1 (0.6)	0
Epistaxis	1 (0.6)	0
Gingival bleeding	0	1 (0.6)
Bronchial hemorrhage	0	1 (0.6)
Infect diseases	2 (1.1)	5 (2.9)	0.643	0.423†
Cerebral infarction	1 (0.6)	5 (2.9)
Myocardial infarction	1 (0.6)	0
Thrombotic diseases	0	2 (1.2)		0.242‡
Venous thrombosis	0	1 (0.6)
Arterial thrombosis	0	1 (0.6)
Graft failure	9 (5.1)	7 (4.0)	0.206	0.650∗
Death	1 (0.6)	2 (1.2)	0.001	0.984†

Values are presented as numbers (%).

^∗Indicates Pearson χ² test.

^†Represents continuity correction test.

^‡Represents Fisher's exact test.

Laboratory indicators

We compared the laboratory indicators at 3 months after kidney transplantation. We found that there was no significant difference in the levels of creatinine, urea nitrogen, neutrophils, platelets, lymphocytes, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol between the two groups (P > 0.05). There was a significant difference in the maximum platelet aggregation rate induced by arachidonic acid (P < 0.001), cholesterol (CHOL) (P = 0.028), and low-density lipoprotein cholesterol (LDL-C) (P = 0.003) [Table 5].

Table 5 - Comparison of laboratory indicators of the kidney transplantation recipients at 3rd months after renal transplantation.

Variables	Aspirin group (n = 178)	Control group (n = 173)	Statistical values	P values
Creatinine (μmol/L)	100.0 (86.2, 113.0)	102.0 (85.0, 127.0)	−1.492	0.136
Urea nitrogen (mmol/L)	7.9 (6.4, 9.6)	7.8 (6.2, 9.0)	−1.200	0.230
Neutrophils (×109/L)	3.8 (2.5, 4.9)	3.6 (2.6, 4.7)	−0.367	0.714
Platelets (×109/L)	198.5 (156.0, 238.8)	184.0 (146.0, 223.0)	−1.618	0.106
Lymphocytes (×109/L)	1.2 (1.0, 1.8)	1.3 (0.8, 1.8)	−0.689	0.491
C-reactive protein (mg/L)	0.5 (0.5, 0.8)	0.5 (0.5, 1.0)	−1.053	0.294
PAR (%)	38.1 ± 13.9	50.5 ± 13.6	−8.409	<0.001∗
Cholesterol (mmol/L)	4.0 (3.5, 4.6)	4.2 (3.6, 4.9)	−2.203	0.028
Triglycerides (mmol/L)	1.6 (1.2, 2.2)	1.6 (1.1, 2.0)	−0.115	0.909
HDL-C (mmol/L)	1.2 (1.0, 1.3)	1.2 (1.0, 1.4)	−1.277	0.202
LDL-C (mmol/L)	2.0 (1.6, 2.5)	2.2 (1.8, 2.8)	−2.930	0.003

Continuous variables are presented as median (the lower quartile, the upper quartile) or mean ± standard deviation.

^∗Refers to independent sample t-test, others were tested by Mann–Whitney U test.HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; PAR: Platelet aggregation rate.

Discussion

The development of TRAS is influenced by multiple factors, including older age of the donor or the recipient (>50 years old), diabetes, hypertension, cytomegalovirus infection, delayed graft function, acute rejection, donor cold ischemia time >24 h, the application of vascular clamp device and fashions of anastomosis, as well as atherosclerosis which could be obvious in older donors, or could develop many years post-transplantation, etc.^[6,7,23] The prolonged and recurrent exposure to immune responses and adverse stimulations after renal transplantation triggers localized inflammation with persistent vascular injury, endothelial dysfunction, aggressive intimal hyperplasia, and an accelerated atherosclerotic process, leading to stenosis of the renal artery.^[24] At the same time, post-transplantation traumatized endothelium releasing pro-inflammatory cytokines and chemokines is prone to different degrees of microthrombi formation by activation of platelets and the coagulation cascade, further aggravating stenosis even occlusion. This might also explain why TRAS occurs commonly close to the site of surgical anastomosis and relates to the suture line or post-anastomotic turbulence of blood flow. Endovascular treatment of TRAS by PTA or insertion of a stent is invasive and high-cost. Therefore, studies are expected to focus more on prevention and prophylaxis than on treatment. A small retrospective study indicated that dipyridamole, an anti-coagulant, can reduce the occurrence of TRAS.^[25] In contrast, aspirin not only has the antiplatelet effect but also suppresses inflammatory response, inhibits atherosclerosis, protects vascular endothelial cells,^[10,14-16] making it possible to prevent TRAS.

The previous study about the application of aspirin in renal transplant recipients focused on treating chronic allograft nephropathy, preventing microthrombi formation to improve renal function, and reducing cardiovascular events.^[26-29] Ponticelli and Campise^[30] recently reported that inflammatory status is a well-established major risk factor for the onset of cardiovascular disease and graft fibrosis in transplanted kidney patients, and they proposed several drugs to control the inflammatory state of the graft including low-dose aspirin. Additionally, their article mentioned that prospective trials evaluating these drugs have not been performed in kidney transplantation. Considering that previous retrospective studies in our center initially confirmed the efficacy of aspirin for the prevention of TRAS,^[20] we further designed this prospective randomized controlled study. Our trial fills this gap in the literature. And this trial not only is further strong evidence that aspirin is effective in preventing TRAS, but also lays the groundwork for future investigation about the mechanisms of aspirin for protecting renal allograft and its vessels.

In this study, no significant differences were found in the baseline characteristics between the two groups, except for renal artery anastomosis. Indeed, patients with the grafted renal artery anastomosed to the internal iliac artery at baseline demonstrated a significantly higher incidence of TRAS compared to those with other anastomosis in the present study, in accordance with previous studies.^[17] However, the stratified analysis found that in the internal iliac artery anastomosis group, the aspirin group reduced the risk of c-TRAS by 80% compared to the control group (HR: 0.20, 95% CI: 0.04–0.90). So, the imbalance in anastomosis could not influence the kidney transplantation population in the same type of anastomosis and the validity of results in this study. Although there was no statistical difference between the two groups in the comparison of id-TRAS, the incidence of c-TRAS was lower and statistically significant in the aspirin group compared with the control group (2.8% vs. 11.6%, P < 0.05), confirming the effectiveness of aspirin in preventing TRAS.

There is a possible increased risk of hemorrhagic clinical events, especially gastrointestinal bleeding or peptic ulcer, known to be associated with aspirin use. When determining whether low-dose aspirin is appropriate for an individual recipient, the benefit must be weighed against this potential risk. In a decade-long nationwide study in Sweden of patients with chronic viral hepatitis, the use of low-dose aspirin did not significantly increase the risk of gastrointestinal bleeding compared with no aspirin use.^[31] Another study on the use of aspirin in the treatment of coronary artery disease after liver transplantation for cirrhosis showed that the use of aspirin therapy was not associated with an increased risk of acute variceal hemorrhage, gastrointestinal bleeding, or worsening anemia.^[32] Overall in this study, aspirin treatment was well tolerated with few episodes of clinical events. Despite a slight trend to more hemorrhagic clinical events with aspirin therapy in line with what would be expected, all aspirin-related clinical events were non-serious, generally mild, and highly curable. Importantly, the observed bleeding complications showed no significant difference compared with the control group. The consistency of findings in our study and previous studies in this domain was reassuring.

Although the differences of infarct diseases and thrombotic diseases in the two groups should be interpreted with caution due to no statistical significance, they might indicate a possible trend requiring longer-term follow-up in recipients, and the benefits of aspirin in preventing blood clots are well supported by the literature.^[29,33-36] In addition, this was also evidenced by the statistically significant difference between the two groups in terms of the rate of arachidonic acid-induced platelet aggregation at 3 months post-transplantation. Concurrently, biochemical indicators showed that recipients in the aspirin group had lower CHOL and LDL-C values, which predicted that aspirin, to some extent, could protect renal artery endothelial cells and prevent atherosclerosis by improving blood lipids, thus preventing the progression of TRAS. Therefore, a low-dose aspirin for the prevention of TRAS was shown to be not only safe but also of potential additional long-term benefits, unless a contraindication was documented. The mechanistic question of how aspirin prevents and delays the onset of TRAS by maintaining the surrounding environmental homeostasis of the endothelium in the transplanted renal artery will be the next step in our research.

In summary, our study demonstrates for the first time that the administration of low-dose aspirin for the early post-transplantation period is effective, feasible, and safe in preventing TRAS. Further work exploring the exact molecular mechanisms underlying this result is needed. Finally, further multicentric double-blind studies are required to validate our results.

Funding

This work was supported by grants from the Project of Science and Technology of Henan Province (No. 202102310438), the Joint construction project of Henan Medical Science and Technology Research Plan (No. LHGJ20210042), and the Foundation of Henan Educational Committee (No. 22A320012).

Conflicts of interest

None.