The Importance of Arteriovenous Fistula Management in Kidney Transplant Recipients Arteriovenous fistula (AVF) is the preferred hemodialysis access because of its superior durability and lower infection and mortality rates compared with arteriovenous grafts and central venous catheters. In the United States, approximately 63.7% of the patients with end-stage kidney disease rely on AVF for maintenance hemodialysis, underscoring the importance of consistent evaluation and intervention to preserve patency. However, recent evidence indicates that AVF may raise the risk of heart failure through insidious cardiac remodeling with a reported de novo occurrence of 10.2% and 18.3% at 1 and 3 years after kidney transplantation, respectively.1 Despite this, health care providers remain hesitant to recommend ligation considering fistula is an insurance policy in the event of loss of graft function and hemodialysis reinstitution. Specifically, it was shown that only 4.6% of the patients in the United States undergo vascular access ligation after kidney transplantation with significant center-level variation.2 This practice variation is important because cardiovascular disease is a significant driver of mortality beyond 1 year post-transplant, and even a minor increase in disease burden could have a disproportionate impact on the quality of life and life expectancy of this vulnerable population. The Cardiac Impact of AVF on Kidney Transplant Recipients AVF is believed to trigger cardiac remodeling by lowering the mean arterial pressure and causing organ hypoperfusion and renin-angiotensin-aldosterone axis/sympathetic system overactivation. The resultant volume overload leads to pulmonary hypertension, cardiac hypertrophy, decreased ejection fraction, and heart failure over time. Unfortunately, ascribing cardiac remodeling solely to this pathophysiology may not be entirely accurate in hemodialysis patients because of multiple confounding factors such as concurrent hemodynamic changes related to the hemodialysis procedure and chronic fluid overload due to inadequate ultrafiltration or patient nonadherence to fluid restrictions. Observational, prospective, and retrospective studies in predialysis populations provide insight into the impact of arteriovenous fistulas on heart structure and function. The presence of preemptive arteriovenous access placement was identified as the main risk factor for heart failure (odds ratio = 9.54) in patients with advanced CKD before starting dialysis.3 Furthermore, in a longitudinal magnetic resonance study of patients with stage 5 CKD, it was found that 6 months after AVF creation, cardiac output increased by 25% and left ventricular mass by 12.7%.4 Intriguingly, pretransplant treatment with hemodialysis was associated with a higher risk for de novo heart failure post-transplant when compared with pretransplant peritoneal dialysis.5 These findings call into question the role of functioning fistulas in developing cardiac failure. AVF Ligation Can Mitigate Cardiac Remodeling Randomized controlled trials (RCTs) suggest that fistula ligation may reverse maladaptive cardiac remodeling in kidney transplant recipients. In the most significant RCT by Rao et al., kidney transplant recipients with stable graft function were randomly assigned to AVF ligation or no intervention after the first 12 months of transplantation. Baseline and repeat cardiac magnetic resonance imaging was performed on all participants after 6 months. The repeat imaging showed that the left ventricular mass had decreased by 22.1 g (P < 0.001) and the left ventricular mass index by 11.8 g (P < 0.001) in the AVF ligation group. In addition, significant improvement was also observed in the left ventricular end-diastolic and systolic volumes, cardiac output, cardiac index, atrial volumes, and N-terminal pro–B-type natriuretic peptide in the ligation group (P < 0.01).6 Although the clinical significance of this left ventricular attenuation is not fully realized, existing literature suggests a favorable and independent effect on all-cause and cause-specific mortality. Importantly, an analysis of the Framingham Heart Study Offspring Cohort members without prevalent cardiovascular or kidney disease demonstrated the potential benefits of aggressively preventing left ventricular hypertrophy. In this study, participants underwent cardiovascular magnetic resonance for left ventricular mass and geometry assessment and were followed prospectively for incident cardiovascular disease. Every 10-g/m2 increment in the left ventricular mass index was linked with a 33% increase in cardiovascular disease risk.7 Hetz et al. in a pilot RCT further corroborated the hypothesis that prophylactic AVF ligation immediately after kidney transplantation can prevent de novo heart failure. High-output heart failure attributable to high-flow fistula was reported in five of 13 (38.5%) patients in the control group (no ligation). In the intervention group, no patient presented clinical or echocardiographic findings of heart failure in the 24-month follow-up period.8 Risk Stratification for Cardiac Failure in Kidney Transplant Recipients with Patent AVF Efforts have been made to stratify the cardiac failure risk in kidney transplant recipients with patent AVF using tools such as echocardiographic evaluation and measurement of the fistula flow. Global longitudinal strain (GLS), a new echocardiographic strain measurement, permits early detection of left ventricular systolic dysfunction even in the presence of normal ejection fraction and appears to be one of the first parameters to be affected by the flow of the fistula. In a recent study, Blanchard et al. showed that GLS was correlated with fistula flow (Qa) and fistula flow to cardiac output ratio (Qa/CO) (R=0.331, P = 0.023 and R=0.380, P = 0.008, respectively). A cutoff value of 33% for Qa/CO allowed the detection of significant alteration in GLS indicative of myocardial dysfunction with a sensitivity of 92% and specificity of 66%.9 Moreover, although a specific fistula flow cutoff value conferring a high risk of cardiac failure is still debated, numerous studies have shown that AVF with a blood flow exceeding 1500 ml/min are at a heightened risk. Recommendations for AVF Management in Kidney Transplant Recipients Taken together, patent fistulas constitute an additional burden for the cardiovascular system of kidney transplant recipients. Available data suggest that fistula ligation in recipients with stable kidney function may reduce the heart failure risk. Hence, providers need to be cognizant of the potential deleterious cardiac impact of AVF and be vigilant for early signs of evolving cardiac failure and pulmonary hypertension. We recommend a systematic evaluation of kidney transplant recipients with echocardiograms and sequential fistula flow measurements starting at 6–12 months after transplantation to decide who may benefit from prophylactic fistula ligation (Figure 1). The decision may merit multidisciplinary input from transplant nephrology, transplant surgery, and cardiology. In the risk-benefit analysis, extra weight should be placed on the expected graft survival, patient characteristics, and vascular access history. Graft survival prediction tools using artificial intelligence have shown promising performance and can be used to guide decision making.10 At our center, we have developed a low threshold to recommend prophylactic ligation starting at 12 months after transplantation if risk factors for heart failure are present such as Qa>1500 ml/min, CO/Qa >33%, or echocardiographic findings consistent with myocardial dysfunction or pulmonary hypertension. We also select ligation if an indication for surgical evaluation of an AV fistula arises at any point after transplantation, such as steal syndrome, aneurysm, or infection. In summary, although large-scale outcome studies are needed to confirm the benefit of prophylactic ligation after kidney transplantation, current evidence suggests that careful, individualized evaluation and intervention could confer cardiovascular protection.Figure 1.: Step-wise evaluation of arteriovenous fistula (AVF) after kidney transplantation. ECHO, echocardiogram; GDMT, guideline-directed medical therapy; GLS, global longitudinal strain; PAH, pulmonary arterial hypertension; Qa, fistula flow; Qa/CO, fistula flow to cardiac output ratio.Disclosures K.A. Agarwal's spouse is employed by CareDx. M. Pavlakis reports consultancy for Memo Therapeutics, Merck, Transplant Solutions, and Vertex Pharmaceuticals; research funding as site PI for APOLLO study, site PI for CareDx OKRA study, and site PI on trial for Trugraf Genomics study TRULO; grant funding from CareDx and Transplant Genomics; an advisory or leadership role for Moderna Study Safety Review Committee; and other interests or relationships with EBSCO Industries Inc.—content writer, Leukemia and Lymphoma Society—New England Board of Directors, and OPTN/UNOS Chair of Kidney Transplantation Committee. The remaining author has nothing to disclose.