Association Between Vascular Access Creation and Deceleration of Estimated Glomerular Filtration Rate Decline in Late-Stage Chronic Kidney Disease Patients Transitioning to End-Stage Renal Disease

Keiichi Sumida; Miklos Z. Molnar; Praveen K. Potukuchi; Fridtjof Thomas; Jun Ling Lu; Vanessa A. Ravel; Melissa Soohoo; Connie M. Rhee; Elani Streja; Kunihiro Yamagata; Kamyar Kalantar-Zadeh; Csaba P. Kovesdy

Disclosures

Nephrol Dial Transplant. 2017;32(8):1330-1337. 

In This Article

Discussion

In this retrospective cohort study of late-stage NDD-CKD patients transitioning to dialysis, we compared changes in eGFR slopes between the pre- and post-AVF/AVG period overall and in patients stratified by AVF/AVG maturation. We found a significant deceleration of eGFR decline after AVF/AVG creation independent of its maturation status, whereas eGFR decline accelerated in the last 6 months prior to dialysis in patients without an AVF/AVG. These findings were similarly observed in selected subgroups and were robust even after adjustment for known confounders and in the propensity-matched cohort.

Timely creation of a primary arteriovenous access before the anticipated need for hemodialysis therapy allows adequate time for the access to mature as well as sufficient time for a potential vascular access revision procedure if the first attempt fails.[2] A functional AVF/AVG provides convenient dialysis access to circulation with adequate blood flow, and also has certain systemic physiological benefits.[12,13,25–29] In pre-dialysis CKD patients, a successful AVF creation has been shown to be associated with reduction in arterial stiffness and BP, and an increase in stroke volume, left ventricular ejection fraction and cardiac output, in contradistinction to those with an unsuccessful AVF creation.[12,13] These beneficial physiological effects have been suggested to be partly attributable to the functional and structural alterations of vascular endothelium such as increased production of nitric oxide and cell proliferation in response to the shear wall stress downstream from the fistula, leading to the mitigation of arterial stiffening both locally and systemically.[13,15] These studies, however, have largely focused on the cardiovascular effects of a functional AVF; to our knowledge, there is only one study which investigated its potential physiological effects on kidney function. Golper et al.[14] evaluated the rate of eGFR decline before and after successful AVF creation among 123 patients with advanced NDD-CKD, and demonstrated that there was a significant slowing of eGFR decline from −5.9 to −0.5 mL/min/1.73 m2/year after AVF creation. They concluded that there may be an association between successful AVF creation and the slowing of eGFR decline, based on the assumption of potential 'downstream' vasodilatory effects of a functional AVF on renal vascular beds through vascular endothelium, which may lead to perfusion of previously under-perfused renal tissues, resulting in a recruitment of untapped renal functional reserve.[30] There seems to be biological plausibility for the observed deceleration of eGFR decline after the creation of a functional AVF; however, the previous study by Golper et al.[14] examined the change in eGFR slopes only in patients with successful AVF creation, and hence, no conclusion could be drawn as to whether the observed association was specific to AVF creation and attributable to the physiological effects of a mature access versus confounding factors observed in the late-stage NDD-CKD that may influence eGFR independent of vascular access maturation.

Our study is the first to examine the change in eGFR slopes before and after AVF/AVG creation separately by its maturation status, and in contrast to non-AVF/AVG patients, and the first to provide evidence regarding the association between AVF/AVG creation and a deceleration of eGFR decline independent of AVF/AVG maturation status. Because we detected improved outcomes after AVF/AVG creation even in patients with a non-mature AVF/AVG, we must consider the possibility that the deceleration of eGFR decline associated with AVF/AVG creation may be attributable to factors unrelated to the physiological effects of a mature vascular access, such as more attentive nephrologist care and improved patient health status or behavioral compliance with therapy. Although most of the patients agreeing to a timely AVF/AVG creation are compliant by nature, we cannot rule out the possibility of their compliance and/or nephrologist care improving even further after AVF/AVG creation and hence positively affecting their disease course. Nonetheless, there still seem to be other plausible physiological mechanisms that could explain the potential reno-protective effects of AVF/AVG creation even in those patients whose vascular access is not mature enough for successful hemodialysis cannulation.

Recently, growing evidence from experimental and clinical studies has indicated that remote ischemic preconditioning (RIPC), represented by limb ischemic preconditioning by alternating cycles of inflating and deflating BP cuffs on either the arm or leg, is a promising and feasible approach for renoprotection and prophylaxis against acute kidney injury (AKI).[31–34] It has been postulated that even a brief ischemic stimulus of a remote site releases RIPC-induced humoral factors such as adenosine, erythropoietin or nitric oxide into the systemic circulation, which subsequently protects other target organs, including the kidney.[31,34] Other underlying mechanisms of RIPC may include systemic immune modulation and anti-inflammatory effects on immune-competent cells following RIPC.[34] In addition, autonomic reflexive and other neurogenic pathways that are stimulated by the release of opioid and bradykinin may be involved in RIPC-induced reno-protective effects.[34] Moreover, the reno-protective effects of RIPC have been shown to be more beneficial in patients with preexisting CKD and comorbid conditions who are at higher risk for developing superimposed AKI.[35] Regarding AVF/AVG creation, temporal and repetitive clamping of the feeding artery and permanent ligation of small arterial branches are inevitable or necessary during the surgical procedure.[36] Furthermore, the AVF/AVG creation itself may cause local limb ischemia in the distal part of access,[36] and hence the post-operative state of AVF/AVG creation could be considered as a similar state to RIPC. Therefore, the sequential local ischemic conditions caused by the creation of AVF/AVG could also serve as a potential explanation for the observed deceleration of eGFR slopes after AVF/AVG creation in advanced CKD patients, even in patients with a non-mature AVF/AVG.

Although many studies have demonstrated that hemodialysis through an arteriovenous access is associated with better clinical outcomes than a central venous catheter,[5–10] a number of barriers must be overcome to achieve successful arteriovenous access construction; chief among these is late referral of patients for permanent access creation.[37] In addition, there remains uncertainty regarding the benefits of early arteriovenous access creation as the preferred management strategy in pre-dialysis CKD patients progressing to ESRD, given the risk of premature access-related complications and undefined cost-effectiveness of the procedure.[38] Given these circumstances, our results could be a novel incentive for advanced CKD patients to pursue timely creation of an AVF/AVG.

Our study is notable for its large sample size of late-stage NDD-CKD patients transitioning to dialysis, and for being representative of veterans in the entire geographic United States; however, several limitations need to be acknowledged. This study was observational, and hence, the results do not allow us to infer causality but merely associations between AVF/AVG creation and eGFR slopes. Most of our patients consisted of male veterans; therefore, the results may not be generalizable to women or patients from other geographical areas. Data related to AVF/AVG blood flow measured in a quantitative manner were not available; hence, the AVF/AVG maturation status was defined based on procedure codes and the type of vascular access at the time of dialysis initiation. Information about vascular access procedures was obtained from diagnostic codes recorded during care in a VA facility. Thus, there might be misclassification of vascular access status, such that patients who had undergone AVF/AVG creation at a non-VA facility which did not mature would have not been captured and might have been misclassified as comparators. However, this misclassification would tend to underestimate the true change in eGFR slopes of patients without an AVF/AVG. We adjusted predicted eGFR slopes for a variety of important covariates as potential confounders, but we cannot eliminate the possibility of unmeasured confounders, such as proteinuria, muscle mass, changes in volume status and quality of care, which might affect eGFR slopes over time.

In conclusion, the creation of an AVF/AVG is associated with an improvement in the rate of eGFR decline over time in advanced CKD patients irrespective of AVF/AVG maturation status. These findings highlight the potential beneficial effects of AVF/AVG creation on kidney function and suggest that timely creation of AVF/AVG prior to dialysis may contribute to delayed onset of dialysis initiation in advanced CKD patients. Further studies are needed to clarify the underlying mechanisms.

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