Kidney transplant recipients have traditional and nontraditional risk factors which can lead to coronary artery disease and sudden death with a functional graft loss. Aspirin has been used traditionally for prevention of cardiovascular and cerebrovascular accidents. It has beneficial effects in secondary prevention of cardiovascular events in general population. Its use for primary prophylaxis is still disputed. Bleeding and theoretical risk of nephrotoxicity are the major concerns about its use. The data on aspirin in kidney transplant population is sparse. This review will focus on various pros and cons of aspirin use for prevention of cardiovascular events in kidney transplant recipients and a way forward.
Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients (KTR). The age of KTR is increasing over time from 35-45 years in 1988 to 50-64 in 2012 [
Aspirin inhibits platelet function by acetylation of the platelet cyclooxygenase (COX) [
Nonsteroidal anti-inflammatory medications (NSAIDs) are well known for nephrotoxicity, gastritis, and bleeding. Aspirin, being a NSAID, can also potentially cause these complications. Nephrotoxicity in the setting of kidney transplantation is even more important as the recipient only has one functional kidney. We will review these potential complications in this section.
Previous studies have shown conflicting results about the use of aspirin and the risk of chronic kidney diseases. Some earlier studies have shown that the use of aspirin is associated with chronic kidney disease [
Aspirin has been used for prevention of renal vein thrombosis in KTR. In the majority of these studies, no adverse outcome was observed in terms of graft dysfunction. Aspirin has been shown to improve graft survival in a retrospective study and a meta-analysis [
Studies on aspirin nephrotoxicity.
Author | Journal/Year | Study Design / Methods | Finding |
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Morlans M et al. [ | Br J Clin Pharmacol / 1990 | Case control study/ They studied non-narcotic analgesics taken at least every other day for 30 days or longer and compared with control. | Overall odds ratiobefore the first symptom of renal disease was 2.89 (95% CI, 1.78 to 4.68). The risk increased in relation to the use duration. |
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Fored CM et al. [ | N Engl J Med / 2001 | Case control study / 926 newly diagnosed chronic kidney disease patients were interviewed and logistic-regression models were used to estimate the relative risks of disease-specific types of chronic renal failure associated with the use of various analgesics (aspirin, acetaminophen) | Use of either of the drug was associated with a 2.5 times increase risk of chronic kidney disease. |
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Ibáñez L et al. [ | Kidney Int / 2005 | Case control studies / Five hundred and eighty-three cases and 1190 controls were included in the analysis. | Long-term use of any analgesic was associated with an overall odds ratio of 1.22 (95% CI, 0.89-1.66). Risks for aspirin was 1.56 (1.05-2.30). The risk of chronic kidney diasesae stage V associated with aspirin was related to the cumulated dose and duration of use, and it was particularly high among the subset of patients with vascular nephropathy as underlying disease [2.35 (1.17-4.72)]. |
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Perneger TV et al. [ | N Engl J Med /1994 | Case control of study of 716 Chronic Kidney Disaese –V. Control were of similar from Maryland, Virginia, West Virginia, and Washington, D.C. | Authors found increased risk of chronic kidney disease-V in a dose-dependent fashion with acetaminophin. A cumulative dose of 5000 or more pills containing NSAIDs was also associated with an increased odds of ESRD (odds ratio, 8.8). Aspirin was not associated with increased risk of chronic kidney disease. |
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Sandler DP et al. [ | N Engl J Med / 1989 | Multicenter case-control study to examine the use of analgesic as cause of chronic kidney disease. A total of 554 adults with newly diagnosed kidney disease and 516 matched control subjects selected randomly from the same area of North Carolina. | The risk of renal disease was highest in daily users of phenacetin (odds ratio, 5.11; confidence interval, 1.76 to 14.9, after adjustment for the effects of other analgesics). The risk of renal disease was also increased in daily users of acetaminophen; after adjustment for the use of aspirin and phenacetin, the odds ratio was 3.21 (confidence interval, 1.05 to 9.80). There was no increased risk in daily aspirin users (adjusted odds ratio, 1.32; confidence interval, 0.69 to 2.51). |
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Kurth at al. [ | Am J Kidney Dis / 2003 | Prospective cohort study of healthy male physicians. Self-reported use of aspirin, acetaminophen, and other nonsteroidal anti-inflammatory drugs (NSAIDs) was classified as never (<12 pills during the study period), 12 to 1,499 pills, 1,500 to 2,499 pills, and 2,500 or greater pills during the study period. | Authors concluded that occasional to moderate analgesic intake of aspirin, acetaminophen, or NSAIDs does not appear to increase the risk for decline in kidney function during a period of 14 years in healthy physicians. |
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Rexrode KM et al. [ | JAMA / 2001 | Prospective cohort study / Data was taken from the Physicians’ Health Study, which lasted 14 years from September 1982 to December 1995 with annual follow-up. | Multivariable analyses adjusted for age; body mass index; history of hypertension, elevated cholesterol, and diabetes; occurrence of cardiovascular disease; physical activity; and use of other analgesics, the relative risks of elevated creatinine level associated with intake of 2500 or more pills were 0.83 (95% confidence interval [CI], 0.50-1.39; P for trend =.05) for acetaminophen, 0.98 (95% CI, 0.53-1.81; P for trend =.96) for aspirin, and 1.07 (95% CI, 0.71-1.64; P for trend =.86) for other nonsteroidal anti-inflammatory drugs. No association was observed between analgesic use and reduced creatinine clearance. |
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Agodoa LY et al. [ | Am J Kidney Dis / 2008 | Cross-sectional analysis of National Health and Nutrition Examination Survey conducted in 1999-2002. Age-standardized prevalence in habitual analgesic users and non-habitual analgesic users and multivariable-adjusted odds ratios (ORs) were measured. | Habitual analgesic use of single or multiple products was not associated with increased prevalence of albuminuria or reduced eGFR as compared to non-habitual analgesic user. |
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Curhan GC et al. [ | Arch Intern Med / 2004 | Prospective Health Nurse Study. Informations were gatherered via a mailed questionnaire in 1999 about lifetime use of acetaminophen, aspirin, and NSAIDs and provided blood samples in 1989 and 2000. | Acetaminophen use was associated with an increased risk of a GFR decline of at least 30 mL/min per 1.73 m(2) (P trend =.01) and a GFR decline of 30% or greater (P trend<.001), but aspirin and NSAID use were not. |
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Okada S et al. [ | PLoS One. 2016 Jan | Randomized controlled trial (RCT), the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, to evaluate low-dose aspirin as primary prevention for CVD in patients with type 2 diabetes. Patients with negative urine dipstick albumin of the JPAD trial in were followed in a cohort study after the RCT period was completed. | Low-dose aspirin did not increase the risk of positive urine dipstick albumin. There were no significant differences in annual changes in eGFR between the groups (aspirin, -0.8±2.9; no aspirin, -0.9±2.5 ml/min/1.73 m(2)/year). |
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Hansen HP et al. [ | Diabetes Care / 2000 | Randomized double-blind crossover trial of 17 type 1 diabetic patients with microalbuminuria to study the effect of aspirin on proteinuria | Use of 150 mg ASA daily does not have any impact on albumin excretion rate or glomerulofilteration rate in type 1 diabetic patients with microalbuminuria. |
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Gaede P et al. [ | Nephrol Dial Transplant/2003 | Randomized, double-blind, crossover trial, of 31 type 2 diabetic patients with elevated levels of AER (>30 mg/24 h) were, in random order, given ASA (150 mg/day) for 4 weeks followed by placebo for 4 weeks with a 2 week washout period or vice versa. | Low-dose treatment with 150 mg aspirin daily does not have any impact on albumin excretion rate or GFR in type 2 diabetic patients with micro- or macroalbuminuria. |
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Hopper AH et al. [ | Nephrol Dial Transplant / 1989 | Double-blind crossover pilot study to study the effect of administration of aspirin-dipyridamole and reduction of proteinuria in diabetic nephropathy. | 24 hour urinary protein excretion significantly reduced during aspirin-dipyridamole administration from a geometric mean (range) of 1.9 (0.4-7.7) g/24 h to 1.4 (0.5-9.9) g/24 h (P vaslue less than 0.05). |
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Grotz W et al. [ | Transplantation / 2004 | Retrospective, multivariate analysis toassess the effect of low-dose aspirin treatment (100 mg/day) on allograft function and survival of 830 renal transplant recipients. | Allograft survival was significantly longer in patients receiving low-dose aspirin therapy compared with patients receiving no aspirin treatment (n=205, 13.8 +/- 2.6 vs. 7.8 +/- 0.3 years, n=625; adjusted relative risk=0.443, 95% confidence interval |
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Cheungpasitporn W et al. [ | J Nephropathol / 2017 | Metanalysis of | Aspirin reduced the risk of allograft |
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Ali H et al. [ | Experimental and Clinical Transplantation / 2017 | Retrospective analysis of 82 patients on low-dose aspirin 75 mg | Aspirin use was not |
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Murphy GJ et al. [ | Br J Surg /2001 | A prospective consecutive series of 105 cadaveric renal transplants treated with aspirin 150 mg daily for the first 3 months after transplantation was compared with an untreated historical control group (n = 121). Needle protocol core biopsies were performed. | Rate of significant primary allograft thrombosis in patients treated with aspirin (none of 105) compared with that in the control group (six (5 per cent) of 121; P = 0.03) was found. No differences in renal function or 2-year allograft survival between the two groups was found. Aspirin-treated patients had a lower incidence of chronic allograft nephropathy at 1 year than controls, however P value was not significant. |
Low-dose aspirin has been associated with increased risk of bleeding in the general population [
Summary of studies on aspirin and bleeding risk
Author | Journal / Year | Study Design / Method | Finding |
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Robertson AJ et al. [ | Nephrol Dial Transplant / 2000 | Retrospective study of effect of 75 mg once a day starting immediately before and continuing for 1 month post-transplant for prophylaxis against renal vein thrombosis. | Out of 480 patients, post biopsy bleeding was present in 8 (1.6%), early post- transplant bleeding in 3 (1%) and re-exploration for bleeding in 3 (1%). |
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Murphy GJ et al. [ | Br J Surg / 2001 | A consecutive series of 105 cadaveric renal transplants treated with aspirin 150 mg daily for the first 3 months after transplantation was compared with an untreated historical control group (n = 121) for prevention of renal vein thrombosis. | Post biopsy macroscopic hematuria was 9 percent in aspirin treated group and 7 percent in the control group. |
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Hachem LD et al. [ | TransplInt / 2017 | Case–control study of patients receiving a kidney transplant / To study postoperative surgical-site hemorrhage after kidney | Bleeding was not significant in KTR with antiplatelet as compared to those who were not on antiplatelet. |
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Weng F et al. [ | Am J Transplant / 2016 | Retrospective cohort study of kidney transplant recipients who received a transplant from 2008-2014 and had a pre-transplant diagnosis of coronary artery disease and receiving dual antiplatelet. | Transfused during transplant hospitalization 30.3% in those on dual antiplatelet as compared to 15.7% who were not on dual antiplatelet. (P value 0.03) |
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Bailey PD et al. [ | Austin J Nephrol Hypertens / 2015 | A retrospective cohort study of consecutive adult living- and | Blood transfusion was required in 34.6% within 5 days of kidney transplantation. Perioperative blood transfusion was given in 27.8% of patients in the NONE group, 52.2% of cases in the DUAL group, and42.2% of cases in the ASA group (p<0.01) suggesting an association of ASA and DUAL with blood transfusion on univariate analysis. Antiplatelet therapy, either as DUAL or ASA alone, was not associated with reoperation for bleeding (1.0%, 0.0%, 1.5% p = 0.79) |
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Shullo MA et al. [ | Pharmacotherapy / 2002 | Retrospective chart review of thirteen patients who had received enoxaparin within 10 days of kidney or kidney-pancreas transplantation. Major bleeding events were defined as intracranial or retroperitoneal bleeding, or a decrease in hemoglobin of greater than 2 g/dl. | Nine (69%) of the 13 patients had confirmed major bleeding events and required blood transfusions. |
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Atwell TD et al. [ | AJR Am J Roentgenol. / 2010 | The objective of our study was to report the incidence of bleeding after imaging- | The incidence of bleeding in kidney biopsy, 0.7%; highest than the rest of organs. |
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Baffour FI et al. [ | Journal of vascular and interventional radiology JVIR / 2017 | Retrospective analysis to determine if patient aspirin exposure and timing affect bleeding risk after renal allograft biopsy. Four groups were analyzed which included no aspirin exposure 10 days, exposure within 8-10 days, exposure within 4-7 days and 0-3 days. | Aspirin use was not significantly associated with increased risk of bleeding complication except for use of 325 mg of aspirin within 3 days of biopsy (any complication OR 3.87 |
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Lees JS et al. [ | Clin Kidney J. 2017 | Retrospective data review /This study aimed to describe the incidence of major bleeding after biopsy in a single center over a 15-year period and examine factors associated with major bleeding. Aspirin was routinely continued | Aspirin was taken by 327 / 1509 patients. There was no significant increase in the risk of major bleeding (P=0.93). |
Various models have been used to predict cardiovascular events in the general population. These include the Framingham Risk Score, the Reynolds Risk Score, the Prospective Cardiovascular Münster Heart Study (PROCAM), the Systematic Coronary Risk Evaluation system (SCORE), and the QRISK 1 and 2 [
Evidence for aspirin use in KTR for primary prophylaxis is still lacking. Guidelines differ in the recommendation of aspirin use in primary prophylaxis. The United States Preventive Services Task Force recommends low-dose aspirin for the primary prevention of cardiovascular disease in adults aged 50-59 years who have a 10% or greater 10-year CVD risk [
Patients who suffered from acute coronary syndrome or ischemic strokes are always at risk of a second cardiovascular event. Percutaneous intervention stabilizes acute events only. Aspirin therapy is needed for further prevention of events. The role of aspirin in reducing CVD mortality and repeat events after acute myocardial infarction was first demonstrated in the second International Study of Infarct Survival (ISIS-2) trial [
Newer-generation (everolimus/zotarolimus) drug eluting stents are associated with lower risk of thrombosis and coronary events than the older first-generation stents [
The timing of transplant surgery and other noncardiac surgeries in patients on antiplatelets therapy needs to assess risk vs. benefit of stopping antiplatelet and doing that surgery. It is wise to have a multidisciplinary meeting including cardiologist, anesthetist, surgeon, and transplant physician before taking a decision. For patients who need percutaneous intervention (PCI) and are planning for transplantation within 1 year, the 2012 guidelines [
The recommended daily dose for aspirin is 81 mg (range, 75 to 100 mg) for prevention of secondary prophylaxis [
Guidelines for use of aspirin for secondary prophylaxis.
Clinical Scenarios | Recommendations |
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Coronary artery disease stented with first generation bare metal stent | Dual antiplatelets for 4-12 weeks [ |
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Coronary artery disease stented with first generation drug eluting stent | Dual antiplatelet for ≥ 12 months [ |
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Transplant surgery | Transplant surgery within 3 months of bare metal stent and within 12 months of drug eluting stent should not be performed [ |
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Stable coronary artery disease stented with newer-genration (everolimus / zotarolimus) drug eluting stents | Dual antiplatelet therapy for 6 months [ |
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Coronary artery disease stented with low risk of bleeding and having newer-genration (everolimus / zotarolimus) drug eluting stents or bare metal stent | Guidelines recommend continuation of dual antiplatelet beyond 1 month in baremetal stent and more than 6 months in drug eluting stent in patients who are at low risk of bleeding [ |
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Coronary artery disease stented with high risk of bleeding and having newer-genration (everolimus / zotarolimus) drug eluting stents or bare metal stent | Discontinuation of P2Y12 inhibitor therapy after 3 months may be reasonable in those with high risk of bleeding |
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Patient with acute coronary syndrome (NSTEMI / STEMI) treated baremetal stent or newer generation drug eluting stent | Dual antiplatelet should be given for atleast 12 months [ |
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Patients with acute coronary syndrome treated with stenting, who has tollerated dual antiplatelets without a bleeding complication, and who are not at high risk of bleeding | Continuation of dual antiplatelets beyond 12 month may be reasoable [ |
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Patients with acute coronary syndrome treated with stenting and at high risk of bleeding | Discontinuation of P2Y12 inhibitor after 6 months may be reasonable [ |
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Patients with ACS who never underwent revascularization or fibrinolytic therapy | They should be treated with dual antiplatelets for at least 12 months [ |
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ST elevated myocardial infarction | Should be continued on dual antiplatlet for a minimum period of 14 days [ |
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Patients planning for transplantation in one year and needing PCI | Angioplasty with bare metal stenting followed by 4-12 weeks of dual antiplatelets [ |
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KTR on dual antiplatelets needing emergency surgery | Hold thienopyridine for 5 days and continuing aspirin preoperatively [ |
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Waiting time for kidney transplantation and other elective surgery after PCI | Wait for 3 months in case of bare metal stenting and 6 months for drug eluting stenting [ |
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Dose of aspirin | The recommended dialy dose for aspirin is 81 mg (range, 75 to 100 mg) for prevention of secondary prophylaxis [ |
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Proton pumpinhibitors | Proton pump inhibitors (PPIs) are recommended in patients with dual antiplatelets with increased risk of bleeding. This includes advance age, concomitant use of warfarin or non steroidal antiinflammatory drugs (class 2a evidence). Routine use of PPIs in patients at low risk of bleeding is not recommended (class III, no benefits) [ |
While starting aspirin, one has to keep in mind risks versus benefits. The benefits of aspirin can be offset by the associated risk of bleeding. This is of particular concern in KTR, who are being considered for primary prevention with aspirin. KDIGO 2009 practice guidelines for prevention of cardiovascular events in KTR recommend aspirin in patients with diabetes or cardiovascular disease. However, this is based on very poor quality of evidence [
Aspirin should be used in established coronary artery disease for secondary prevention. Low-dose aspirin has not been shown to cause nephrotoxicity. The beneficial effects of aspirin are offset by high risk of major bleeding in primary prevention in the general population. Due to lack of evidence at the moment, it cannot be recommended for primary prevention of cardiovascular events in KTR. The risk of bleeding should be assessed in all recipients before starting aspirin. KTR have many risk factors other than the traditional risk factors. There is a need for development of a cardiovascular risk prediction score targeting the kidney transplant population. A randomized control trial is also needed to assess the beneficial effect of primary prophylaxis with aspirin in the kidney transplant population. The final decision on using aspirin should be made after balancing the specific characteristics of each patient taken into account the patient’s risk for bleeding and the concomitant pathologies in each case.
The authors declare that they have no conflicts of interest.