Rilparencel (Renal Autologous Cell Therapy-REACT®) for Chronic Kidney Disease and Type 1 and Type 2 Diabetes: Phase 2 Trial Design Evaluating Bilateral Kidney Dosing and Redosing Triggers.

INTRODUCTION: Autologous cell-based therapies (CBT) to treat chronic kidney disease (CKD) with diabetes are novel and can potentially preserve renal function and decelerate disease progression. CBT dosing schedules are in early development and may benefit from individual bilateral organ dosing and kidney-dependent function to improve efficacy and durability. The objective of this open-label, phase 2 randomized controlled trial (RCT) is to evaluate participants' responses to rilparencel (Renal Autologous Cell Therapy-REACT®) following bilateral percutaneous kidney injections into the kidney cortex with a prescribed dosing schedule versus redosing based on biomarker triggers. METHODS: Eligible participants with type 1 or 2 diabetes and CKD, eGFR 20-50 mL/min/1.73 m2, urine albumin-to-creatinine ratio (UACR) 30-5,000 mg/g, hemoglobin >10 g/dL, and glycosylated hemoglobin <10% were enrolled. After a percutaneous kidney biopsy and bioprocessing ex vivo expansion of selected renal cells, participants were randomized 1:1 into two cohorts determined by the dosing scheme. Cohort 1 receives 2 cell injections, one in each kidney 3 months apart, and cohort 2 receives one injection and the second dose only if there is a sustained eGFR decline of ≥20 mL/min/1.73 m2 and/or UACR increase of ≥30% and ≥30 mg/g, confirmed by re-testing. CONCLUSION: The trial is fully enrolled with fifty-three participants. Cell injections and follow-up clinical visits are ongoing. This multicenter phase 2 RCT is designed to investigate the efficacy and safety of rilparencel with bilateral kidney dosing and compare two injection schedules with the potential of preserving or improving kidney function and delaying kidney disease progression among patients with stages 3a-4 CKD with diabetes.

Drug-coated balloons and dialysis vascular access: is there light at the end of the tunnel . . .

This commentary uses the negative results of the PAVE (Paclitaxel-coated Balloons and Angioplasty of Arteriovenous Fistulas) study to (i) discuss the role of drug-coated balloons in the armamentarium of therapies for dialysis vascular access stenosis and (ii) suggest a more patient centered, individualized, and precision medicine-based approach for the future care of patients with dialysis vascular access dysfunction.

Advances in Endovascular Salvage.

Endovascular salvage plays an important role in dialysis access care. Angioplasty using standard high- and ultrahigh-pressure balloon is the mainstay of therapy, while the use of cutting balloons and balloons designed to deliver pharmacologically active agents to the site of recurrent stenosis is demonstrating improved performance for specific targets that have to be further defined. Stents and stent grafts are additional tools for use at access segments predisposed for inward remodeling such as the cephalic arch or basilic swing point. The juxta-anastomotic segment has particular relevance in maturation of autogenous accesses as well as maintenance of access flow volume. Depending on the location of the access in the forearm or upper arm, and which artery is feeding into the access vein, any type of balloon angioplasty and stent or stent graft placement may be used to establish and maintain patency. Successful management of dialysis access options relies on preservation of venous real estate during the chronic kidney disease phase of kidney disease as well as on knowledgeable evaluation of arm veins and the access by physical examination, bed side ultrasound, and angiographic studies.

The Lutonix AV Randomized Trial of Paclitaxel-Coated Balloons in Arteriovenous Fistula Stenosis: 2-Year Results and Subgroup Analysis.

PURPOSE: To present final, 2-year results of a randomized trial comparing paclitaxel-coated vs uncoated balloon angioplasty following vessel preparation with ultra-high-pressure percutaneous transluminal angioplasty (PTA) in hemodialysis arteriovenous fistulae (AVFs). MATERIALS AND METHODS: Twenty-three sites enrolled 285 subjects with dysfunctional AVFs located in the arm. Before 1:1 randomization, successful vessel preparation was achieved (full waist effacement, < 30% residual stenosis). Follow-up was clinically driven except for a 6-month office visit. RESULTS: Ninety-six of 141 subjects in the drug-coated balloon (DCB) arm and 111 of 144 in the control arm completed the study. Target lesion primary patency (TLPP) rates for the DCB and control groups were 58% ± 4 vs 46% ± 4 (P = .02) at 9 months, 44% ± 5 vs 36% ± 4 (P = .04) at 12 months, 34% ± 5 vs 28% ± 4 (P = .06) at 18 months, and 27% ± 4 vs 24% ± 4 (P = .09) at 24 months, respectively. Mean time to TLPP event for subjects with an event was longer for DCBs (322 vs 207 d; P < .0001). Fewer interventions were needed to maintain target lesion patency in the DCB group at 9 months (P = .02) but not at 12 (P = .08), 18 (P = .13), or 24 months (P = .19). The noninferiority safety target was met at all intervals (P < .01). Mortality did not differ between groups (P = .27). Post hoc analyses showed equivalent DCB effect in all subgroups. CONCLUSIONS: Two-year results demonstrate long-term safety and variable efficacy of DCB angioplasty in AVFs.

Evidence-Based Strategies and Recommendations for Preservation of Central Venous Access in Children.

Children with chronic illness often require prolonged or repeated venous access. They remain at high risk for venous catheter-related complications (high-risk patients), which largely derive from elective decisions during catheter insertion and continuing care. These complications result in progressive loss of the venous capital (patent and compliant venous pathways) necessary for delivery of life-preserving therapies. A nonstandardized, episodic, isolated approach to venous care in these high-need, high-cost patients is too often the norm, imposing a disproportionate burden on affected persons and escalating costs. This state-of-the-art review identifies known failure points in the current systems of venous care, details the elements of an individualized plan of care, and emphasizes a patient-centered, multidisciplinary, collaborative, and evidence-based approach to care in these vulnerable populations. These guidelines are intended to enable every practitioner in every practice to deliver better care and better outcomes to these patients through awareness of critical issues, anticipatory attention to meaningful components of care, and appropriate consultation or referral when necessary.

Drug Coated Balloon Angioplasty in Failing AV Fistulas: A Randomized Controlled Trial.

BACKGROUND: Restenosis remains a problem in hemodialysis access interventions. Paclitaxel-coated balloons have shown promise in reducing access-related restenosis in small trials. The primary hypotheses for our multicenter trial were superior effectiveness at 180 days and noninferior safety at 30 days of a drug-coated balloon compared with conventional angioplasty for treatment of dysfunctional arteriovenous fistulas. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This randomized trial enrolled 285 patients with dysfunctional arteriovenous fistulas at 23 centers. Grafts, central venous stenoses, thrombosed fistulas, and immature fistulas were excluded. All patients received angioplasty of the lesion responsible for access dysfunction. After successful angioplasty (≤30% residual stenosis), lesions were treated with either a paclitaxel-coated balloon or an uncoated control balloon of similar design to the drug-coated balloon. Access function during follow-up was determined per centers' usual protocols; reintervention was clinically driven. The primary efficacy outcome assessment was done at 6 months, and the safety assessment was done within 30 days of the procedure. Prespecified secondary end points included assessment of postintervention target lesion primary patency and access circuit primary patency at 6 months. RESULTS: The 180-day end point was not met with target lesion primary patency (71%±4% for the drug-coated balloon and 63%±4% for control; P=0.06), representing a difference of 8%±6% (95% confidence interval, -3% to 20%). Access circuit primary patency did not differ between groups. Interventions to maintain target lesion patency were fewer for the drug-coated balloon at 6 months (0.31 versus 0.44 per patient; P=0.03). The primary safety noninferiority end point was met and did not differ between groups (P=0.002). CONCLUSIONS: Paclitaxel-coated balloon-assisted angioplasty did not meet the primary effectiveness end point at 180 days compared with conventional angioplasty. Both arms showed equivalent safety (ClinicalTrials.gov number NCT02440022).

Venous Hemodialysis Catheters and Cardiac Implantable Electronic Devices: Avoiding a High-Risk Combination.

End-stage renal disease is frequently accompanied by cardiac comorbidity that warrants treatment with a cardiovascular implantable electronic device (permanent pacemaker or implantable cardioverter-defibrillator). In the United States, chronic hemodialysis (HD) population, cardiac implantable devices are present in up to 10.5% of patients; a venous HD catheter is utilized for blood access in 18% of prevalent patients. The concomitant presence of a venous HD catheter and cardiovascular implantable device creates a high-risk circumstance, with potential for causing symptomatic central venous stenosis, and for developing complicated endovascular infection. This dangerous combination may be avoided for many patients by utilizing nondialysis methods for management of advanced chronic kidney disease, initiating dialysis without venous catheter access, or managing cardiac rhythm disorders without use of transvenous cardiac implantable electronic devices. In those situations where the combination of a venous HD catheter and cardiac implantable device is unavoidable, there are strategies to minimize duration of venous catheter access, and to reduce risks for infectious complications. It is essential for nephrologists and cardiologists to understand the indications, alternatives, and risks involved with venous HD access and cardiac implantable devices. Coordinated management of renal disease and cardiac rhythm disorders has potential to minimize risks, improve outcomes, and substantially reduce the cost of care.

Prospective, Randomized, Concurrently-Controlled Study of a Stent Graft versus Balloon Angioplasty for Treatment of Arteriovenous Access Graft Stenosis: 2-Year Results of the RENOVA Study.

PURPOSE: To present final, 2-year data from randomized comparison of an expanded polytetrafluoroethylene stent graft (SG) and percutaneous transluminal angioplasty (PTA) for treatment of arteriovenous graft (AVG) anastomotic stenoses. MATERIALS AND METHODS: A 28-site, prospective, controlled US study enrolled 270 patients with malfunctioning AVG anastomotic stenoses of ≥ 50%; 138 patients underwent SG placement, and 132 underwent PTA alone. Follow-up imaging and intervention were event-driven. RESULTS: The study was completed by 191 patients (97 SG, 94 PTA). Five patients were lost to follow-up or withdrew; 74 patients died during the study (38 SG, 36 PTA). At 12 months, treatment area primary patency (TAPP) was SG 47.6% versus PTA 24.8% (P < .001), access circuit primary patency (ACPP) was SG 24% versus PTA 11% (P = .007), and index of patency function (IPF) was SG 5.2 months/intervention ± 4.1 versus PTA 4.4 months/intervention ± 3.5 (P = .009). At 24 months, TAPP was SG 26.9% versus PTA 13.5% (P < .001), ACPP was SG 9.5% versus PTA 5.5% (P = .01), and IPF was SG 7.1 months/intervention ± 7.0 versus PTA 5.3 months/intervention ± 5.2; estimated number of reinterventions before graft abandonment was 3.4 for SG patients versus 4.3 for PTA patients. There were no significant differences in adverse events (P > .05) except for restenosis requiring reintervention rates of 82.6% in PTA patients versus 63.0% in SG patients (P < .001). CONCLUSIONS: At 2 years, SG use provided a sustained, greater than 2-fold advantage over PTA in treatment area and overall access patency. Time to subsequent intervention was longer in the SG group.

Cardiovascular implantable electronic devices in hemodialysis patients: prevalence and implications for arteriovenous hemodialysis access interventions.

Cardiovascular implantable electronic devices (CIEDs) are frequently utilized in hemodialysis patients. CIED leads are typically implanted via the subclavian vein resulting in stenosis and venous hypertension. We studied 1235 chronic hemodialysis patients under the care of our nephrology practice. For each, we determined the presence of a CIED, indication for implantable cardioverter-defibrillator (ICD), and type of hemodialysis access. Records were reviewed to identify all interventions performed on the access circuit and the central veins specifically. A CIED was present in 129 patients (10.5%), including ICDs in 75 (6.1%) and pacemakers in 54 (4.4%). The access circuit intervention rate was 1.48/access year (AY) and was similar when a CIED was ipsilateral (1.53/AY) or contralateral (1.44/AY) to arteriovenous access (p = 0.477). The rate of central venous interventions was greater in the ipsilateral (0.59/AY) versus contralateral group (0.28/AY), (p < 0.001). Fifty-four of 59 patients with ipsilateral access and CIED required <2 interventions per AY, but six failed angioplasty and required access ligation. None had superior vena cava stenosis requiring intervention. We conclude that there is a high prevalence of CIEDs in our HD patients. Ipsilateral CIED and arteriovenous access results in higher central venous intervention rates compared with contralateral cases; overall access circuit intervention rates are similar.

Cardiovascular implantable electronic device leads in CKD and ESRD patients: review and recommendations for practice.

Cardiovascular implantable electronic devices (CIEDs) are frequently utilized for management of cardiac dysrhythmias in patients with chronic kidney disease or end-stage renal disease receiving hemodialysis. The survival benefit from use of implantable cardioverter defibrillators in patients with CKD or ESRD is not as clear as in the general population, particularly when used for primary prevention of sudden cardiac death. Transvenous CIED leads are associated with central vein stenosis resulting in significant adverse consequences for existing or future arteriovenous access. Venous hypertension from CIED lead-related central vein stenosis is a challenging clinical problem and may require repeated percutaneous interventions, replacement of the CIED, or creation of alternative arteriovenous access. Infections associated with transvenous CIED leads are more frequent and associated with worse outcomes in patients with renal disease. Epicardial CIED leads or other nontransvenous devices may reduce complications of both central venous stenosis and endovascular infection in these vulnerable patients. Consensus recommendations are offered for avoidance and management of complications arising from the use of CIEDs and arteriovenous hemodialysis access.

Management of the immature autogenous arteriovenous fistula.

A high-quality autogenous arteriovenous fistula provides the optimal access for hemodialysis. Following initial surgical construction of a fistula, the maturation process is driven by hemodynamic, cellular, and humoral factors that must result in increased blood flow, vessel dilation, and thickening of the vessel wall before the fistula can be successfully used for dialysis needle access. Different demands are placed on each fistula depending on the individual patient's hemodialysis requirements, which must be clearly understood to properly assess and treat the immature fistula. When spontaneous maturation fails to achieve a functional fistula, additional surgical or minimally invasive interventional procedures may be necessary to enhance the maturation process. Various techniques have been reported to achieve successful fistula maturation. The purpose of this article is to review the concepts of fistula maturation and the interventions that may be performed in cases where there is failure to mature spontaneously.

Central vein stenosis or occlusion associated with cardiac rhythm management device leads in hemodialysis patients with ipsilateral arteriovenous access: a retrospective study of treatment using stents or stent-grafts.

PURPOSE: Symptomatic central vein stenosis commonly occurs when cardiac rhythm management device (CRMD) leads are placed via the subclavian vein ipsilateral to arteriovenous (AV) hemodialysis (HD) access. The purposes of this study were to determine the outcomes, complications, and patency following stenting of CRMD lead-associated central vein stenosis or occlusion, and to determine the effect of stents on CRMD function. METHODS: Fourteen HD patients with AV access and an ipsilateral CRMD were treated with stents for symptomatic central vein stenosis or occlusion following inadequate response to angioplasty from January 2005 to December 2009. Subsequent access interventions, complications, and outcomes were reviewed retrospectively. Cardiology records were examined to assess CRMD function. RESULTS: Treatment of stenosis or occlusion with angioplasty and stenting resulted in 100% procedural success and no complications. At 6 and 12 months, respectively, primary patency rates were 45.5% and 9.0%; primary-assisted patency rates were 90.9% and 80.0%; secondary patency rates were 100% and 90.0%. There were 42 repeat interventions performed in 12 patients; five received additional stents. The mean number of subsequent interventions was 3.2 per patient (2.1 per patient-year). All CRMD testing demonstrated normal function with no device or lead failure. Seven of the 14 subjects died resulting in a 35.3% annual mortality rate. No deaths were attributable to dysrhythmia or CRMD failure and no patient required CRMD removal or exchange. CONCLUSIONS: Placement of stents for CRMD lead-associated stenosis or occlusion yields high success and low complication rates with no effect on CRMD function. Patency rates are similar to those reported in other series of central venous stents.

Guidelines for venous access in patients with chronic kidney disease. A Position Statement from the American Society of Diagnostic and Interventional Nephrology, Clinical Practice Committee and the Association for Vascular Access.

At the time of hemodialysis vascular access evaluation, many chronic kidney disease patients already have iatrogenic injury to their veins which impedes the surgical construction of an arteriovenous fistula (AVF). Achieving the important goal of a greater prevalence of arteriovenous fistulae in the US hemodialysis population will require identification of those patients prior to reaching end-stage renal disease and an educational and procedural system for preserving their veins.