A Randomized Trial of Liposomal Prednisolone (LIPMAT) to Enhance Radiocephalic Fistula Maturation: A Pilot Study

Abstract

Patients on maintenance hemodialysis (HD) require a reliable vascular access; however, only half of newly created radiocephalic arteriovenous fistulas (RCAVF) can be used for HD without additional procedures to promote maturation and up 25% fail to provide adequate vascular access for HD.1Voorzaat B.M. van der Bogt K.E.A.A. Janmaat C.J. et al.Arteriovenous fistula maturation failure in a large cohort of hemodialysis patients in the Netherlands.World J Surg. 2018; 42: 1895-1903Crossref PubMed Scopus (14) Google Scholar The need for subsequent creation of upper arm arteriovenous fistulas (AVFs) and arteriovenous grafts may decrease if maturation can be improved. Currently, no pharmacological treatments have been proven to improve clinical maturation of AVFs. Although the underlying pathophysiology of nonmaturation is incompletely understood, impaired outward remodeling and neointimal hyperplasia in the venous outflow tract seem to contribute.2Rothuizen T.C. Wong C. Quax P.H.A. et al.Arteriovenous access failure: more than just intimal hyperplasia?.Nephrol Dial Transplant. 2013; 28: 1085-1092Crossref PubMed Scopus (88) Google Scholar Studies in murine and porcine models of AVF failure revealed a pronounced inflammatory response in the venous outflow tract in the early phase after AVF surgery.3Dundon B.K. Torpey K. Nelson A.J. et al.The deleterious effects of arteriovenous fistula-creation on the cardiovascular system: a longitudinal magnetic resonance imaging study.Int J Nephrol Renovasc Dis. 2014; 7: 337-345PubMed Google Scholar Recent studies suggest that this inflammatory response impairs AVF maturation.4Bezhaeva T. de Vries M.R. Geelhoed W.J. et al.Relaxin receptor deficiency promotes vascular inflammation and impairs outward remodeling in arteriovenous fistulas.FASEB J. 2018; 32: 6293-6304Crossref Scopus (5) Google Scholar Pegylated liposomes have emerged as an attractive tool to facilitate selective delivery of drugs to inflamed tissues with a highly permeable microvasculature, where liposomes are being phagocytized by macrophages. It has a potent and long-lasting anti-inflammatory effect at sites of inflammation, while minimizing exposure of noninflamed tissues. In a murine model of AVF failure, we have demonstrated that liposomal prednisolone inhibits inflammation of the juxta-anastomotic vein and improves outward remodeling of the venous outflow tract.5Wong C. Bezhaeva T. Rothuizen T.C. et al.Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model.Sci Rep. 2016; 6: 30439Crossref PubMed Scopus (17) Google Scholar We hypothesized that maturation of RCAVFs in humans can be improved by inhibition of juxta-anastomotic inflammation using liposomal prednisolone. In the Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation (LIPMAT) study, we aimed to assess if liposomal prednisolone improves maturation of RCAVFs and if it can be safely administered to patients with end-stage renal disease. The design of this multicenter randomized placebo-controlled trial has been reported earlier in detail,6Voorzaat B.M. van Schaik J. van der Bogt K.E.A. et al.Improvement of radiocephalic fistula maturation: rationale and design of the Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation (LIPMAT) study–a randomized controlled trial.J Vasc Access. 2017; 18: S114-S117Crossref PubMed Scopus (5) Google Scholar and methods are available in the Supplementary Materials. From April 2016 through May 2018, 109 patients were planned for RCAVF creation and assessed for study eligibility. A total of 64 patients were excluded for known exclusion criteria from their medical history (n = 24), not consenting to study participation (n = 34), or late referral (n = 6, Figure 1). Of the remaining 45 patients who provided informed consent, 32 were randomized (Table 1). Reasons for dropout are shown in Figure 1. After randomization, but before treatment, 2 patients experienced clinical events constituting exclusion criteria. The remaining 30 patients received the study treatment. The trial was stopped prematurely in May 2018 because of slow enrollment.Table 1Baseline characteristics of 29 patients in the LIPMAT study by treatment groupBaseline characteristicsPlacebo (n = 13)Liposomal prednisolone (n = 16)Total (n = 29)Age, yr70 ± 8.565 ± 1267 ± 11Gender Female5 (38)1 (6)6 (21) Male8 (62)15 (94)23 (79)Race Caucasian11 (85)13 (81)24 (83) Hindustani Surinamese1 (8)2 (13)3 (10) Moroccan0 (0)1 (6)1 (3) Asian1 (8)0 (0)1 (3)Cause of renal failure Diabetes mellitus4 (31)6 (38)10 (35) Renal vascular disease5 (39)4 (25)9 (31) Glomerulonephritis3 (23)2 (13)5 (17) Interstitial nephropathy1 (8)2 (13)3 (10) Cystic kidney disease0 (0)2 (13)2 (7)Comorbidities Diabetes mellitus7 (54)7 (44)14 (48) Coronary artery disease6 (46)4 (25)10 (35) Peripheral artery disease4 (31)3 (19)7 (24) Cerebrovascular disease5 (39)4 (25)9 (31)Medication ACE inhibitor1 (8)6 (38)7 (24) Angiotensin 2 receptor blocker8 (62)5 (31)13 (45) Loop diuretic8 (62)9 (56)17 (59) Aldosterone receptor antagonist0 (0)1 (6)1 (3) Beta blocker10 (77)8 (50)18 (62) Calcium channel blocker8 (62)11 (69)19 (66) Platelet inhibitor4 (31)10 (63)14 (48) Anticoagulant2 (15)3 (19)5 (17) Vitamin D12 (92)13 (81)25 (86)ACE, angiotensin-converting enzyme; LIPMAT, Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation.Data are reported as mean ± SD or n (%). Open table in a new tab ACE, angiotensin-converting enzyme; LIPMAT, Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation. Data are reported as mean ± SD or n (%). The primary end point was assessed in 29 patients. The distal cephalic diameter was 3.9 mm (95% confidence interval, 2.7–5.8 mm) in the placebo group and 3.7 mm (95% confidence interval, 3.0–5.3 mm) in the treatment group (P = 0.88). No significant results were observed for secondary end points (Table 2).Table 2Effect of liposomal prednisolone on primary and secondary end points in 29 patients in the LIPMAT studyEnd pointsPlacebomedian (IQR)Liposomal prednisolonemedian (IQR)P (Mann-Whitney U)6 wk Cephalic veinJuxta-anastomotic diameter, mm3.9 (2.7–5.8)3.7 (3.0–5.3)0.88Elbow diameter, mm5.5 (4.7–6.7)5.0 (4.0–6.1)0.47Mid upper arm diameter, mm4.0 (2.3–5.3)4.8 (4.1–5.4)0.22 Radial arteryJuxta-anastomotic diameter, mm3.6 (2.9–4.2)3.6 (3.0–4.0)0.83Flow, ml/min456 (277–688)406 (300–772)0.81 Brachial arteryFlow, ml/min523 (342–985)550 (417–1201)0.793 moCephalic vein Juxta-anastomotic diameter, mm4.2 (2.3–6.1)4.9 (3.9–5.8)0.43 Elbow diameter, mm6.2 (4.7–6.9)5.7 (4.4–6.3)0.35 Mid upper arm diameter, mm5.8 (2.8–4.5)5.7 (3.6–6.2)0.83Radial artery Juxta-anastomotic diameter, mm4.0 (2.1–5.0)3.6 (3.0–4.6)1.00 Flow, ml/min546 (110–1037)560 (334–970)0.65Brachial artery Flow, ml/min800 (434–1485)798 (479–1019)0.60IQR, interquartile range; LIPMAT, Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation. Open table in a new tab IQR, interquartile range; LIPMAT, Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation. At the time of assessment of the functional outcomes, 54% of AVFs in the placebo arm and 69% in the liposomal prednisolone arm were successfully used for HD (P = 0.41). Seven patients (44%) in the liposomal prednisolone arm and 4 patients (31%) in the placebo group underwent an endovascular or surgical procedure to achieve RCAVF maturation. During follow-up, in the placebo and liposomal prednisolone groups, respectively 23% and 13% of RCAVFs had failed (P = 0.45). The functional outcome could not be determined for 6 patients, because of loss to follow-up (2 patients who moved abroad) or not initiating HD (Table 3).Table 3Effect of liposomal prednisolone on functional outcomes of RCAVF in 29 patients in the LIPMAT studyFunctional outcomePlacebo (n = 13)Liposomal prednisolone (n = 16)AVF used Without procedures to improve maturation3 (23)4 (25) With procedures to improve maturation4 (31)7 (44)AVF not used Failed due to nonmaturation3 (23)2 (13) Kidney transplantation0 (0)1 (6) Did not reach ESRD1 (8)1 (6) Deceased before ESRD0 (0)1 (6)Loss to follow-up2 (16)0 (0)Values are n (%).AVF, arteriovenous fistula; ESRD, end-stage renal disease; LIPMAT, Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation. Open table in a new tab Values are n (%). AVF, arteriovenous fistula; ESRD, end-stage renal disease; LIPMAT, Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation. No infusion reactions were observed except for 1 subject in the liposomal prednisolone arm who was known to have symptoms of orthostatic hypotension, and experienced mild dizziness without hypotension on postural change during the infusion. The incidence of symptoms related to progressive renal failure and cardiovascular events was similar in both treatment arms (Table 4).Table 4Adverse events reported in the LIPMAT studyAdverse eventsPlacebo (n = 13)Liposomal prednisolone (n = 16)AVF-related events Angiography/angioplasty36 Revision surgery10 Coiling or ligation of collateral veins12 Hematoma or bleeding21 New AVF within 3 mo11 Nerve damage10 Edema10Infusion-related events Orthostatic symptoms (no hypotension)01Renal and metabolic Fluid overload32 Gout10 Uremia (worsening)10 Anemia (worsening)11Cardiovascular Atrial fibrillation/flutter24 Myocardial infarction12 Angina pectoris (worsening)01 Intermittent claudication (worsening)10Infectious AVF site infection01 Cellulitis (non-AVF site)01 Upper airway infection including rhinosinusitis02 Septicemia01 Dental10Other Accidental injury32 Fatigue and sleep disorders44 Liver enzyme abnormalities22 Hyperthyroidism01 Hair loss10 Intoxication01 Aspecific thoracic pain01 Constipation01 Sunburn01 Melanoma10 Gastric pain01 Hematoma non-AVF site01 Urinary catheter placement01Myocardial infarction includes non-ST-elevation myocardial infarction.AVF, arteriovenous fistula; LIPMAT, Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation. Open table in a new tab Myocardial infarction includes non-ST-elevation myocardial infarction. AVF, arteriovenous fistula; LIPMAT, Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation. In the liposomal prednisolone arm, 5 infections were observed in the 3 months of follow-up. One subject was treated with antibiotics due to erythema in the AVF arm, without fever or systemic symptoms. One subject experienced 2 episodes of mild rhinosinusitis that resolved without specific treatment. One subject died 72 days after AVF surgery, because of progressive fluid overload, complicated by septicemia from a possible catheter-related infection or pneumonia. In the placebo group, 1 subject experienced a dental abscess 3 months after AVF surgery. In the LIPMAT study, we evaluated if liposomal prednisolone improves maturation of RCAVFs. The trial was terminated because of slow enrollment after inclusion of 30 of the 80 subjects initially aimed for. We present the study to investigate feasibility and to report preliminary outcomes. Liposomal prednisolone was safe and well-tolerated by patients with end-stage renal disease. No severe infusion reactions were observed and no severe infections were observed within the expected duration of effect of liposomal prednisolone. Liposomal prednisolone did not result in improved RCAVF maturation as measured by ultrasound at 6 weeks and 3 months after surgery. The 62% successful cannulation rate observed in the LIPMAT study was comparable to previous studies on functional AVF maturation.1Voorzaat B.M. van der Bogt K.E.A.A. Janmaat C.J. et al.Arteriovenous fistula maturation failure in a large cohort of hemodialysis patients in the Netherlands.World J Surg. 2018; 42: 1895-1903Crossref PubMed Scopus (14) Google Scholar,7Bleyer A.J. Scavo V.A. Wilson S.E. et al.A randomized trial of vonapanitase (PATENCY-1) to promote radiocephalic fistula patency and use for hemodialysis.J Vasc Surg. 2019; 69: 507-515Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Although the nonsignificant result may be a mere result of a lack of power due to the small sample size, also no trend toward any difference between the treatment and control group was observed. Apart from a lack of statistical power, several factors might explain the lack of therapeutic efficacy of liposomal prednisolone to improve AVF maturation. First, the local concentration of liposomal prednisolone in the vessel wall of the AVF might not have been sufficient to exert a strong anti-inflammatory effect. The local accumulation of liposomal prednisolone could not be examined, as the AVFs could not be sacrificed for examination. In addition, no approved formulation of the compound was available to trace the liposomes in vivo in humans. Second, the inflammatory response in the RCAVF might have been too limited to induce significant local vascular accumulation of the liposomes. Previous clinical studies revealed substantial localization of liposomal prednisolone in the atherosclerotic arterial wall.8der Valk FM van van Wijk D.F. Lobatto M.E. et al.Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration.Nanomedicine. 2015; 11: 1039-1046Crossref PubMed Scopus (93) Google Scholar As the prevalence of atherosclerosis was high in the LIPMAT subjects (Table 1), a significant proportion of liposomal prednisolone may therefore have accumulated in nontarget vessel walls instead of the AVF vein. In future studies, tissue samples of AVFs that failed early may be acquired during surgical revisions and analyzed for liposomal prednisolone content. The extent and timing of venous inflammation after AVF surgery in humans is not fully known. To avoid potential detrimental effects on wound healing, liposomal prednisolone was not administered before surgery. As most of outward remodeling of AVFs has been shown to occur within the first 4 weeks after surgery,9Robbin M.L. Greene T. Cheung A.K. et al.Arteriovenous fistula development in the first 6 weeks after creation.Radiology. 2016; 279: 620-629Crossref PubMed Scopus (65) Google Scholar we aimed to cover this interval by administering the drug at day 1 and 15 after surgery. This might have been too short, with significant inflammation persisting at 4 weeks after surgery. The LIPMAT study was the first to study an anti-inflammatory strategy to improve AVF maturation in humans. We could not demonstrate a clinically significant impact on RCAVF maturation. Future studies are needed to elucidate the role of inflammation in AVF maturation and the clinical promise of liposomal formulations of anti-inflammatory drugs to promote AVF maturation.

Topics & Concepts