Renal Interventions 3 - US

May 2022 Issue 03 www.renalinterventions.net

In this issue:

Reflections on the KDOQI guidelines page 5

Matteo Tozzi

page 12

UKRR:

Latest studies in kidney transplantation

Peritoneal dialysis uptake rises

page 18

page 15

New drug-coated balloon data provide further encouragement in vascular access

US end-stage kidney disease prevalence more than doubles THE NUMBER OF PEOPLE LIVING with end-stage kidney disease (ESKD; prevalent cases) more than doubled between 2000 and 2019—increasing by 118.7%, from 358,247 to 783,594—according to data analysis from the United States Renal Data System (USRDS).

A 41.8% increase in new (incident) cases also occurred during the same period, from 92,660 to 131,422. Diabetes and hypertension were identified as primary causes driving higher percentage changes in prevalent and incident ESKD cases.

The analysis, which is published in a Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention (CDC) also highlights racial and ethnic disparities in US ESKD rates.

Among Asian people, new ESKD cases increased from 2,507 cases in 2000 to 6,256 cases in 2019—a 149.5% increase that was the largest seen in any racial or ethnic group. During the study period, new cases increased from 25,917 to 33,700 among Black people (30% increase), from 11,297 to 20,790 among Hispanic people (84% increase), from 742 to 1,458 among Native Hawaiian or other Pacific Islander people (96.5% increase), and from 51,156 to 67,919 among white people (32.8% increase).

American Indian or Alaska Native people had the smallest increase in new cases, from 1,041 to 1,299, representing a 24.8% increase. The authors attribute the slowing of new cases in this population to targeted interventions funded by the Special Diabetes Program for Indians—a US$150 million annual grant programme established in 1997.

They anticipate that ESKD prevalence will continue to rise due to a growing and ageing population, high rates of hypertension and diabetes, and better survival of patients with ESKD. The continued increase in ESKD case numbers will compound the strain on the healthcare system and lead to higher costs, the authors write.

They note that, in 2019 alone, Medicare spent US$37.3 billion (7% of all paid claims costs) on ESKD, according to USRDS data.

Continued efforts to address risk factors, to prevent or delay ESKD onset, could stabilise or reverse these increasing numbers, the researchers conclude.

Profile:

ESKD cases increased by

118.7 % between

2000 and 2019

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Late-breaking data from clinical trials assessing drug-coated balloon (DCB) technologies have provided encouragement that these alternatives to plain-balloon angioplasty in vascular access care are safe, and can enable sustained freedom from reintervention over time.

Findings from the IN.PACT AV Access (Medtronic) and ISABELLA (MedAlliance) trials were both delivered for the first time at the recent Charing Cross Symposium (CX 2022; 26–28 April, London, UK).

T

he former was presented by Andrew Holden (Auckland City Hospital, Auckland, New Zealand), who disclosed 36-month data from a global randomised controlled trial (RCT) assessing the IN.PACT AV DCB (Medtronic) as part of the CX 2022 Vascular Access Masterclass. In a Podium 1st presentation, Holden told audiences that end-stage kidney disease (ESKD) patients treated with the IN.PACT AV DCB remained intervention-free for longer than those who received a standard percutaneous transluminal angioplasty (PTA). He noted that a “significant difference” in target-lesion primary patency (TLPP) between the trial's DCB and PTA treatment groups was seen through the threeyear follow-up timepoint, maintaining the trend observed in the 24-month IN.PACT AV Access data, which Holden delivered virtually at last year’s CX Symposium.

The investigational device exemption (IDE) trial is seeking to assess the safety and efficacy of the IN.PACT AV DCB, which delivers the antiproliferative drug paclitaxel to inhibit neointimal hyperplasia and treat this leading cause of arteriovenous fistula (AVF) stenosis in ESKD patients. Specifically, the trial is comparing the use of the IN.PACT AV DCB in a treatment group to standard PTA in a control group, and enrolled 330 patients with a de novo or non-stented restenotic native fistula undergoing haemodialysis.

Three-year data from IN.PACT AV Access Building on positive results seen at previous timepoints in this prospective, single-blinded, randomised IDE trial, Holden relayed a TLPP rate of 43.1% in the DCB group, compared to 28.6% in the PTA group, through 36 months.

He also reported that a 21.3% reduction in reinterventions

36-month

IN.PACT AV

ACCESS DATA

TLPP rate:

43.1% DCB

All-cause mortality rate:

v

28.6% PTA

26.6% v 30.8% DCB

PTA

Andrew Holden delivered three-year IN.PACT AV Access results as CX returned to London in April

was associated with DCB use, with 255 reinterventions to maintain TLPP being required through 36 months in the DCB group versus 324 in the PTA group.

Holden then moved on to detail 36-month access circuit primary patency (ACPP) rates—stating that a “similar trend” was observed here, with a rate of 26.4% in the DCB group and 16.6% in the PTA group. He labelled this difference as being “significant” too, and noted a similar reduction (20.7%) in the number of reinterventions required to maintain ACPP within the DCB group. There were 311 necessary reinterventions in the DCB group and 392 in the PTA group.

After briefly alluding to mortality-related safety concerns that have been raised regarding paclitaxel in the past, Continued on page 2

2

Drug-Coated Balloons

New drug-coated balloon data provide further encouragement in vascular access Continued from page 1

Holden reported all-cause mortality findings— following a vital status update—that did not represent a statistically significant difference between the two treatment groups. He noted an all-cause mortality rate of 26.6% in the DCB group and 30.8% in the PTA group, and highlighted the fact that the mortality rate among “all-comer” haemodialysis patients from the United States Renal Data System (USRDS) through three years is higher than in both groups, at 41.9%.

Holden also stated that these findings compare favourably to those seen in the Lutonix AV IDE trial (BD) too, but noted that direct comparisons are difficult to draw because this trial concluded after 24 months. Having shown a sustained and superior performance with DCB versus PTA, IN.PACT AV Access is now “the only randomised pivotal trial of a device treating dysfunctional AVFs to demonstrate consistent and sustained clinical benefit through 36 months”, according to Holden. Summarising the data, he added that ESKD patients in IN.PACT AV Access had a median time to reintervention that was 14.7 months longer when they were treated with DCB compared to PTA. As such, Holden concluded that these findings represent durable, long-term data supporting the use of the IN.PACT AV DCB as “a standard of care” for AVF maintenance in this patient population.

Encouragement in spite of “potentially disappointing” results A second Podium 1st presentation at CX 2022 saw Tjun Tang (Singapore General Hospital, Singapore) deliver late-breaking data from a small-scale pilot trial that indicate “potentially disappointing” results—but, according to Tang, still offer encouragement in the treatment of dysfunctional dialysis accesses with DCBs. Tang presented 12-month findings from the prospective, single-centre ISABELLA trial, which assessed the safety and feasibility of the Selution SLR sirolimus-eluting balloon (MedAlliance) for minimising the effect of neointimal hyperplasia. While its goal of treating AVF stenosis, and ultimately preventing fistula failure, is broadly the same as that of IN.PACT AV Access, a key difference is that the DCB being evaluated in ISABELLA uses sirolimus—an alternative anti-restenotic drug to paclitaxel—to reduce neointimal hyperplasia.

A total of 34 patients were ultimately evaluated at the 12-month follow-up timepoint in ISABELLA, Tang detailed, with the most common indication for intervening being a drop in access flow (61.5% of cases). Moving on to 12-month trial data, he reported a TLPP rate of 44% (16/36 lesions) and an ACPP rate of 31%

(10/32 lesions), which represented decreases from 72% and 63%, respectively, at six months.

In addition, he stated that the overall rate of secondary patency—defined as freedom from access circuit abandonment—was 94.1% (32/34 patients) at 12 months compared to the 97.2% (35/36 patients) observed at six months.

Tang, who was awarded the CX 2022 Senior Clinician Abstract Prize for this presentation, concluded by highlighting “excellent” technical and clinical success rates of 100%, and positive safety outcomes, in the ISABELLA trial. He also relayed that the use of Selution SLR in patients with AVF stenosis appears safe, with no serious adverse events, such as pulmonary embolism or bronchopneumonia, being associated with its use in the trial. And, in terms of efficacy, Tang added that, while the results are “potentially disappointing”, this is a small, exploratory investigation and alluded to possible confounding factors within its findings.

“We do need longer-term data and randomised controlled studies […] if we are going to move forward seriously within this field, and with this technology,” he added. And, speaking to Renal Interventions, Tang noted the importance of being careful when interpreting the results of an exploratory pilot trial—especially one designed to power a future RCT. “I do not think it is actually a setback at all,” he continued. “In fact, I think it is very encouraging. I think the fact we are not getting any serious adverse events with the balloon […] is reassuring.” Tang also told Renal Interventions that, with the exception of the IN.PACT AV Access

“I do not think it is actually a setback at all. In fact, I think it is very encouraging.”

Tjun Tang

trial, a similar drop-off in patency rates between six and 12 months had been observed in several previous studies using paclitaxel to treat dysfunctional dialysis access.

Do the data stack up?

In a discussion at CX 2022, Ounali Jaffer (Barts Health NHS Trust, London, UK)—while clarifying that the IN.PACT AV Access trial was not adequately powered for the information he was seeking—enquired as to whether there was a signal for different areas within the access circuit that may benefit the most from DCB therapy. “The numbers are going to be smaller at three years, but we would say that restenotic lesions certainly have a higher response; the arteriovenous anastomosis and cephalic arch [are observed to benefit most],” Holden responded. “For people who want to start introducing DCB into their practice, these would be lesions that we would be able to support [for DCB treatment].” Following up with a question on the different populations outside of the USA treated in IN.PACT AV Access, Jaffer said: “You had more radiocephalic fistulas, and one of the findings is that there is more neointimal hyperplasia within that area. Do you think that had a profound effect?”

“I was pleasantly surprised because I think, while we know that, with radiocephalic fistulas, the patency is often better than with upper-arm fistulas, the focal stenoses— particularly at the arteriovenous anastomosis with smaller calibre vessels—are the worst performing,” Holden noted.

“And, we found that it is a group that actually differentially did the best. The smaller the calibre of the vessel, the better the drug-coated effect, so it was reassuring to see that.” Here, CX executive board member Nicholas Inston (Queen Elizabeth Hospital, Birmingham, UK) highlighted that the safety signal with paclitaxel-coated balloons seen in the trial was particularly reassuring too.

When asked by Peter Gaines (Sheffield Hallam University, Sheffield, UK) to compare the ISABELLA data with results from IN.PACT AV Access, Tang said that the “all-comer” population of dialysis patients in his trial reflects everyday practice in Singapore—also noting that the lesions observed in patient populations from Asia tend to be greater in number and longer than those seen in European and US studies. “I think the IN.PACT [AV Access] data are fantastic and it is a unique trial in terms of showing a positive effect in its primary endpoint,” Tang continued, but added that the IN.PACT AV Access dataset may be more “sanitised” and stems from a randomised trial as well. ISABELLA is promising, and demonstrated safety, but is still only exploratory, he concluded, stating a belief that, as such, this may be akin to “comparing apples and oranges”.

Robert Jones (Queen Elizabeth Hospital, Birmingham, UK) then pressed Tang on which of the two leading drugs he favours in his everyday practice—paclitaxel or sirolimus. Tang said that, when it comes to AVFs specifically, “all the data there are with paclitaxel”. He noted that he has access to all the established DCBs in his centre, including the MagicTouch sirolimus-coated balloon (Concept Medical), and stated: “My personal feeling would be to just use paclitaxel for the time being—I think there needs to be more data with sirolimus, but the signal we are getting is better.” Tang said this belief is also supported by encouraging results from the MATILDA trial of the MagicTouch device.

For more insight on DCBs, including lessons from the DeVA trial (Boston Scientific), which Jones himself presented at CX 2022, turn to pages 6–7.

Editor-in-chief: Nicholas Inston | Editorial Board: Ziv Haskal, Stephen Hohmann, Robert Jones Publisher: Roger Greenhalgh | Content Director: Urmila Kerslake | Editor: Jamie Bell jamie@bibamedical.com | Design: Terry Hawes, Wes Mitchell Editorial contribution: Jocelyn Hudson, Will Date and Clare Tierney Advertising (EU): Shilpa Suthar shilpa@bibamedical.com | Advertising (US): Nicole Schmitz nicole@bibamedical.com Subscriptions: subscriptions@bibamedical.com | News or advertising queries: Tel: +44 (0)20 7736 8788 Published by: BIBA Publishing, which is a subsidiary of BIBA Medical Ltd BIBA Medical, Europe, 526 Fulham Road, Fulham, London, SW6 5NR, United Kingdom Tel: +44 (0) 20 7736 8788 | BIBA Medical, North America, 155 North Wacker Drive, Suite 4250, Chicago, IL 60606, United States Tel: +1 708-770-7323 Printed by: Micropress Printers Ltd. Reprint requests and all correspondence regarding the newspaper should be addressed to the editor at the United Kingdom address. © BIBA Medical Ltd, 2022. All rights reserved.

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Renal Interventions May 2022 – Issue 3

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KDOQI

KDOQI guidelines: Much-needed overhaul and missed opportunities Scott Trerotola (University of Pennsylvania, Philadelphia, USA), who is set to be awarded a Society of Interventional Radiology (SIR) Gold Medal in June 2022, sits down with Renal Interventions to share his views on the 2019 update to the Kidney Disease Outcomes Quality Initiative (KDOQI) vascular access guidelines.

“I

nterventionists need to read the guidelines. Whilst there will soon be several different tools out there that will be easy to digest, such as a YouTube video or a podcast, there is no substitute for reading the guidelines.

They are the result of a 25-year process of refinement, iteration, research and opinion, so they are the best thing we have got right now.

I love the way that the most recent KDOQI update looks at access as a ‘life plan’—because you cannot take a 99-year-old patient and compare them to a 25-year-old patient who is going to be on dialysis for many years until they eventually, hopefully, get a transplant. And, if you are practising dialysis access interventions, it behoves you and your patient to read those guidelines. Not doing so really means that you are not practising evidence-based medicine—and you should be.

Good medicine struck down by lack of evidence Guidelines by their very nature become a research workbook for the next generation.

There is a fundamental problem associated with any guideline formation. The fact of the matter is that committees are a victim of the evidence team, which changes, and looks at the exact same evidence with a different eye. A lot of evidence had changed by the time the KDOQI guidelines were updated in 2019, and it appears that the evidence team tried to really push as hard as they could, even when there was not all that much evidence. In doing so, they backed off on a lot of existing beneficial guidelines. I am not sure that was the right thing to do. One of the most significant examples of this is in the vessel of choice for dialysis catheters and the order in which they should be used.

Previously, the guidelines essentially said internal jugular first, then external jugular, and we can all agree on that. But, the subclavian vein was listed as being the absolute last choice and it was made clear that it should not be used except in extreme situations. In the latest update, it was actually moved to the third position, on the basis that there was no high-level evidence precluding this—which is insanity, as there will never be a randomised controlled trial of subclavian versus other tunnelled dialysis catheter sites.

It just makes no sense whatsoever and opens the doors for a variety of complications that we literally have not seen (and for good reason) in 30 years. So, if we now allow interventionists to start putting catheters in the subclavian, the harm that is going to come to this patient population is really significant.

Another important element is that they raised transfemoral above translumbar access to the inferior vena cava. Both of these access types have been studied independently and the infection rate is three times higher for transfemo-

ral; it takes a viable access site and/or potential transplant site and, at least a quarter of the time, destroys it by virtue of venous thrombosis. It is also much more of an issue when somebody develops catheter-related venous thrombosis in a femoral vein. All this just does not happen with translumbar access. Of course, not everyone is suitable for translumbar, but—for those who are—it is a much better access route. Now, is this supported by randomised data? No, and it never will be. However, it is supported by level two evidence that the KDOQI evidence team just seems to have ignored. They essentially appear to have refused to consider lower-level evidence.

What we (prior KDOQI teams) did in the past, repeatedly, was to then apply expert opinion, especially when we saw something we felt was good medicine being struck down by lack of evidence. Charmaine Lok (University of Toronto, Toronto, Canada) and team did that elsewhere, such as in dialysis access surveillance—I just wish they had done it in a few more places, but that is my opinion.

One of the areas that the KDOQI guidelines did not go strongly enough on (in fact, backed off on compared to 2006) was promoting and preserving the concept of over-the-wire exchange for infection. We have toed this line throughout the past 20-plus years and we simply do not see people who are crippled by a lack of vascular access options such that all of their upper extremity and lower extremity access has been used up and they are on dialysis with a transhepatic catheter. We see very few people in whom all of their upper extremity veins are gone. And, when we do, they are from outside of the health system. Why? Because we are so careful about over-the-wire exchange preservation of venous access sites. It is well-established that over-thewire exchange is just as effective as removal and replacement. And, yet, we have to fight with infectious disease specialists every single day in our practice. This was an opportunity for the KDOQI team to come out very strongly and really advocate for patients, but it is not as strong as it should be. It is a horrible battle that we should

Scott Trerotola

“One of the areas that the KDOQI guidelines did not go strongly enough on was promoting and preserving the concept of overthe-wire exchange for infection.”

5

not have to fight and having this remain clearly spelled out in the guidelines as it was in 2006 would have helped when communicating with the infectious disease doctors.

Do even well-intended guidelines have inadvertent negative consequences?

Yes, 100%. The ‘Fistula First’ message from the prior guidelines is a great example. We were very strong with that message, which was the right thing to do, and I will stand by this to my dying day. A quarter of all US dialysis patients had fistulas at the time of the first guidelines in 1997; patients across the rest of the world had 60–80%, so the USA was a vast outlier and we needed to fix that. If we had not gone with that message, we would not have gotten the wholesale swing toward us having the 60–70% fistula rate that we have today. But, the pendulum swung a little bit too far, and the guidelines placed a lot of penalties, especially on nephrologists, which caused them to have economic disincentives. Sometimes people could start with a fistula, just for the sake of having a fistula, but it would never get used.

So, I do think that the pendulum needed to swing back a little from the prior guidelines, to say that there are patients in whom grafts are appropriate and there are patients in whom catheters are appropriate. The 2019 KDOQI update reflects this.

We also did not necessarily want very prescriptive thresholds, and one of the big changes in the current guidelines is that they moved away from thresholds and absolute numbers. The primary reason for that was that, in the USA, our Medicare system uses those guidelines as weapons against those on the front lines. When payers weaponise guidelines, then nobody benefits—least of all patients. That is why I think Lok and her team did a very good job of making the update kinder and gentler so that, in the appropriate patient for whom a graft (or catheter) is the right thing to do, when it fits with their life plan, they will get that, as opposed to saying, ‘you have to have a fistula first’. So, yes, guidelines can have negative, unintended consequences.

Common sense and vein preservation We need to preserve access and I still think we do a terrible job of venous preservation in the USA— and probably the rest of the world. The concept of device-created fistulas is in its infancy, but it is very clear that, in the right hands, it can make a massive difference and revolutionise the way dialysis access creation takes place. However, it can only get there if it is coupled with the basic techniques of venous preservation. If everybody had a good forearm cephalic vein, we would not be talking about upper arm fistulas; patients would all get forearm fistulas that would last 10 or 20 years. Forearm fistulas require the least maintenance, have the best outcomes, and patients do not generally get high output heart failure with them. I mean, why not have more of those? The reason is because people that have good cephalic veins have them used up indiscriminately by people putting in intravenous (IV) lines.

Device-created fistulas address that to some extent, as some of the deeper veins are still accessible because they have not been torn up.

But, ultrasound-guided IVs, while very good for patients, are also tearing up those same veins because, again, they are being used indiscriminately by people who should be exercising venous preservation. It is a big-picture thing. I have been promoting and practicing venous preservation for going on 35 years now and you start to see trends. All the new technology in the world will not help us if we do not practice basic things like common sense and vein preservation. Fortunately, this is an area where the current KDOQI team diverged from the evidence team and kept a strong expert opinion-based statement about vessel preservation in the 2019 guidelines.

Indeed, this stance is highlighted as an example of divergence from the evidence team’s recommendations on page S20 of the document.”

Issue 3 – May 2022

Vascular Access

Increased frailty associated with longer time to functional use of vascular access A retrospective analysis of the United States Renal Data System (USRDS) has found that, in patients undergoing haemodialysis treatment, a higher degree of frailty is associated with an increased timeframe for a vascular access to become functional.

As such, writing in the American Journal of Kidney Diseases (AJKD), the analysis’ authors conclude that “frailty may be useful for informing clinical decision-making regarding choice of vascular access”.

THE AUTHORS—KAREN WOO (DAVID Geffen School of Medicine at UCLA [University of California, Los Angeles], Los Angeles, USA) and colleagues—begin by noting that frailty is defined as “a clinically recognisable state of increased vulnerability resulting from ageing-associated decline in reserve and function across multiple physiologic systems, such that the ability to cope with everyday or acute stressors is compromised”. They further claim that, despite the high prevalence of frailty among dialysis patients (with more than 75% of patients older than 60 years of age receiving maintenance dialysis for kidney failure meeting the criteria for frailty), it is unknown whether frailty is directly associated with vascular access failure.

Woo and colleagues set out to elucidate the link between frailty and the time to a mature access via a retrospective, observational study. The study involved patients who initiated haemodialysis through a tunnelled catheter in the USRDS database, from January 2012 through October 2017, and underwent subsequent creation of an arteriovenous fistula or graft.

The investigators followed patients from the placement of their first fistula or graft (time zero) to functional use of the access.

The primary regressor of interest, Woo and colleagues detail, was frailty—meas-

CX 2022

Robert Jones

May 2022 – Issue 3

CFI quartile (hazard ratio [HR]=2.49 [95% confidence interval (CI), 2.41–2.58]).

And, in multivariable analyses, the highest CFI quartile was significantly associated with longer time to functional use of fistulas (HR=0.65 [95% CI, 0.62–0.69]) % % and grafts (HR=0.88 [95% CI, 0.79–0.98]). died within died within Woo and colleagues also note 6 months 12 months that, in their analysis, increased patient frailty was associated with a lower likelihood of functional fistula usage in a dose-response manner, but that the association between frailty and a lower likelihood of functional graft Lowest usage was seen only in the highest frailty CFI quartile. “This is not surprisquartile ing,” they continue, “because the physiologic processes required for fistula maturation can be % % negatively affected by frailty.”

They also claim the results died within died within of their study further emphasise 6 months 12 months the importance of individualising vascular access decision-making based on specific patient characteristics—particularly following recent shifts from ‘fistula-first’ to more patient-centred approaches in clinical practice guidelines.

Moving on to discuss wider implications in terms of US reimbursement policies, they add: “Our results suggest that frailty should be an important consideration in designing these payment models, and many patients, particularly those in the highest frailty quartiles, would not experience the putative benefits of a fistula-first policy.”

In addition, Woo and colleagues detail key limitations of their study—including reduced generalisability due to the requirement of 12 months of Medicare claims availability before initiation of dialysis, and a lack of patient-specific sociodemographic data and data on patient anatomic/surgeon characteristics. The authors conclude their AJKD report by stating: “Frailty, if measured in a systematic clinical assessment, could be used to guide vascular access decision-making, and future studies of vascular access outcomes should include assessment of frailty. Efforts to identify an effective predictive model of fistula maturation Karen Woo failure should be continued.”

Highest frailty quartile

Mortality rates following first haemodialysis session

ured using a claims-based frailty indicator (CFI). This was calculated by modifying a validated, claims-based disability status model created specifically for dialysis populations and “anchored to a well-described frailty phenotype”, the authors add. The CFI yields a continuous value from zero to one, with higher scores indicating greater frailty. The main outcomes assessed in the analysis were overall fistula/graft survival time, and the elapsed time between baseline period (placement of the fistula or graft) and functional use (initiation of haemodialysis using the index vascular access with two needles).

A total of 41,471 patients (aged ≥65 years) met the study’s inclusion criteria including 33,212 who received a fistula, and 8,259 who received a graft, after initiating dialysis. Among those who underwent fistula creation, functional use of the fistula was achieved within the observation period in 18,895 patients (57%), compared with 5,604 patients (68%) in the graft group.

The mean CFI score for the entire patient population was 0.17.

Regarding their results, the researchers report that higher CFI quartiles were associated with a greater rate of mortality, adding that patients in the highest CFI quartile had more than two times the rate of mortality compared with patients in the lowest

22.4

50.5

14

22.4

Curtains for prematurely halted DeVA—or is there a swansong in the data?

Issues with recruitment and a head-on collision with the 2019 paclitaxel furore called a halt on the DeVA trial (Boston Scientific), which is being described as “a casualty of the paclitaxel debate”. Nevertheless, Robert Jones (Queen Elizabeth Hospital, Birmingham, UK) presented an analysis of the primary endpoint of this small, UK-based, multicentre randomised controlled trial—which recruited 92 of a planned total sample size of 186 patients—at the Charing Cross Symposium (CX 2022; 26–28 April, London, UK).

THE REPORT PROMPTED A DISCUSSION AMONG attendees about whether this limited dataset could be mined for meaningful signals or whether it was another “unfortunate but understandable” lost cause among other trials that may have been iced recently due to COVID-19-related challenges.

DeVA set out to assess whether a drug-coated balloon (DCB)—specifically, Ranger (Boston Scientific)—could prolong the time to restenosis, reintervention and associated fistula failure in patients receiving long-term haemodialysis in the 12 months following the procedure.

Its primary objective was the patency of the treated lesion and arteriovenous fistula (AVF) circuit, assessed via a primary endpoint of fistula intervention or failure.

Participants had to have a clinically dysfunctional AVF to be enrolled. The planned follow-up time was 12 months, with a trial duration of three years.

Notably, Jones said that the trial protocol did not mandate predilatation, because this was not an accepted established practice—as it currently is—when the protocol was designed. “We were struggling to recruit […] and then, around that time, we had the [paclitaxel] mortality controversy, which really put the kibosh on this. So, we were backed into a corner and we basically had to end the trial at around 50% recruitment,” he stated.

Image_credit

6

Vascular Access

Plain balloon first and drug-eluting balloon second? The role of DCBs in arteriovenous access Kate Steiner (Stevenage, UK) discusses existing clinical evidence on drug-coated balloons (DCBs) in the treatment of arteriovenous access stenosis—and outlines areas where further data are still needed on how they stack up against more traditional plain-balloon techniques.

F

Image_credit

ailure of maturation in native autologous arteriovenous fistulas (AVFs), fistula thrombosis and dialysis access dysfunction are most often caused by arteriovenous access stenosis. Restenosis after percutaneous transluminal angioplasty (PTA) procedures occurs with patients often requiring repeat treatments to maintain functional patency, but strategies to increase primary patency rates post-PTA would improve outcomes for these patients. Whether DCBs should be a first-line treatment is dependent on there being enough evidence to advocate their use as such for the treatment of arteriovenous access stenosis.

The Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for vascular access recommend a patient-individualised approach to the choice of balloon type for angioplasty based on the operator’s best clinical judgement and expertise.1 They concluded there was insufficient evidence to make a recommendation regarding the use of DCBs in the primary treatment of AVF or arteriovenous graft (AVG) stenosis. A UK consensus approach for managing symptomatic AVF stenosis in haemodialysis patients published in 2021 came to the conclusion that, for stenoses recurring between three and 12 months, the group would have a lower threshold for using DCBs, but there was limited evidence to support their use as a first-line treatment.2 Since both of these publications, further trial data from multicentre randomised controlled trials (RCTs) have been presented and published, but whether this is sufficient to justify the use of DCBs as a first-line therapy remains to be seen. There are conflicting results seen in the trial data. The higher cost of DCBs is another factor and there has been concern about their safety profile since the US Food and Drug Administration (FDA) and

UK Medicines and Healthcare products Regulatory Agency (MHRA) alerts regarding the use of drug-coated devices, and mortality data from their use in the treatment of peripheral vascular arterial disease.

The Lutonix AV investigational device exemption (IDE) clinical trial (BD) was one of Kate Steiner the first large RCTs examining DCBs in arteriovenous access, and the two-year results demonstrated fewer interventions were needed to maintain target-lesion primary patency (TLPP) in the DCB group compared with plain-balloon angioplasty at nine months, where improvement in TLPP was statistically significantly higher.3 And, there were variable differences in patency rates between the groups at other timepoints.

The IN.PACT AV Access clinical trial (Medtronic), comparing DCB angioplasty with plain-balloon angioplasty, demonstrated that, at six months, TLPP was significantly higher within the DCB group at 82.2% compared with 59.5% within the plain-balloon angioplasty group.4 Trial data at 12, 24 and 36 months have now been presented, demonstrating sustained higher patency rates in the DCB group. The PAVE trial was an investigator-led multicentre RCT, comparing the Lutonix DCB catheter (BD) with plain-balloon angioplasty. The results were published in 2021, demonstrating a higher six-month primary patency rate for standard, high-pressure balloon angioplasty at 84.5% versus 71.7% in the DCB group.5 The studies to date demonstrate mixed results. Primary

“There does not appear to be sufficient evidence at present to advocate the primary use of DCBs for all patients and all lesions.”

DeVA data “In summary, we have a prematurely ended, There was a fairly even split between de novo and recur- randomised trial at 50% recruitment, but there are a lot rent stenosis in the recruited cohort, Jones reported. of data there,” he concluded.

The overall primary patency survival plot out to 12 “Bear in mind, we did not predilate, and if we were to months did show separation of the curves in favour redesign this study today, we would have had a predilaof the Ranger balloon, he added—but this did not tation mandate. But, even without predilatation in the reach significance. recruited cohort, we seem to have a significant A subset analysis revealed that, with result in the upper-arm subset. This opens upper-arm fistulas, there was a statistiup questions about what to do with these cally significant improvement in patency data moving forward and, more broadly, at 12 months in favour of Ranger, and this what is the right thing to do with studies trend was even stronger when looking at like this that do not complete.” the brachiocephalic fistula subset.

“We do not really know what to make Unfortunate but understandable of that on its own,” Jones said. “But, noneCX executive board member Nichotheless, it is a subset analysis with a seemlas Inston (Queen Elizabeth Hospital, ingly significant result.”

Birmingham, UK) commented on what he The DeVA investigators did not see a signiffelt was “ethically the right thing to do with Narayan Karunanithy icant difference in the number of reinterventhese data”. tions required in the first 12 months between the control On the one hand, to interpret a non-fully recruited trial and DCB arms although, numerically, there were fewer to its power is challenging but, on the other, to ignore in the DCB arm. “If we extrapolate that out beyond 365 meaningful data signals is also difficult, he noted. “This days—again, going beyond the study protocol—it did start is a real casualty of the paclitaxel debate that is difficult, to approach a more significant result in favour of DCB,” ethically, for those 90-odd patients who have consented,” Jones continued.

Inston said. “The data need to be out there.”

7

patency rates at six months for plain-balloon angioplasty in PAVE are similar to those seen for DCB angioplasty in IN.PACT AV Access. A key similarity of the trials is adequate vessel preparation with effective plain-balloon angioplasty prior to DCB use. None of the above trials have reported a statistically significant difference in mortality between the DCB and plain-balloon angioplasty groups.

The KDOQI guidelines recommend a patient-individualised approach. It appears that some patients respond well to plain-balloon angioplasty, while other patients will benefit from less frequent repeat interventions following DCB angioplasty. There are likely to be contributing variables that may fall into two groups: patient factors and lesion factors. Patient factors are unlikely to be demographic variables, which do not appear to be responsible for significant differences in outcome, but it may be that, in the future, biochemical or genetic markers are identified. Lesion factors include lesion location, de novo versus restenotic lesions, and lesion morphology.

There does not appear to be sufficient evidence at present to advocate the primary use of DCBs for all patients and all lesions. It remains to be seen whether they are effective as first-line agents in all patients and in the treatment of multilevel disease.

References: 1. Lok C, Huber T S, Lee T, et al. KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update. Am J Kidney Dis. 2020; 75(4) Suppl2: 1–164.

2. Jaffer O, Gibbs P, Gibson M, et al. A UK Expert Consensus Approach for Managing Symptomatic Arteriovenous Fistula (AVF) Stenosis in Haemodialysis Patients. Cardiovasc Intervent Radiol. 2021; 44(11): 1736–46.

3. Trerotola S, Saad T, Roy-Chaudhury P. The Lutonix AV randomised trial of paclitaxel-coated balloons in arteriovenous fistula stenosis: 2 year results and subgroup analysis. J Vasc Interv Radiol. 2020; 31(1): 1–14.

4. Lookstein R, Haruguchi H, Ouriel K, et al. Drug Coated balloons for dysfunctional arteriovenous fistulas. N Engl J Med. 2020; 383: 733–42.

5.

K arunanity N, Robinson E, Farhan A, et al. A multicenter

randomized

cont rolled

t r ial

indic ate s

that

paclitaxel-coated balloons provide no benefit for arteriovenous fistulas. Kidney International. 2021; 100: 447–56.

KATE STEINER is a consultant interventional radiologist, and the interventional radiology lead, at East and North Hertfordshire NHS Trust in Stevenage, UK. She has a subspeciality interest in vascular intervention and diagnostic vascular imaging, and in vascular ultrasound in particular. She is a Vascular Access Society of Britain and Ireland (VASBI) council member and maintains a research portfolio.

The author declared no relevant disclosures.

Commenting on the “unfortunate but understandable” halting of the trial, Narayan Karunanithy (Guy’s and St Thomas’ NHS Foundation Trust, London, UK) outlined one of the challenges as “identifying the patients with high enough event rates to prove a significant benefit of the treatment arm”. “Is it worth looking at your data to try and identify patient/access circuit characteristics that were associated with high event rates?” he pondered. “This may be extremely helpful for future trial designs.” Jones concurred that this was a reasonable suggestion, noting: “We have all the data there. It is how to pick it out and what to look at.”

“This opens up questions about what to do with these data moving forward and, more broadly, what is the right thing to do with studies like this that do not complete.”

Robert Jones

Issue 3 – May 2022

8

Fistula Care

Pharmacological approaches to reducing arteriovenous fistula failure rates Sanjay Misra (Rochester, USA) discusses the need for pharmacological approaches that can improve successful, long-term outcomes with arteriovenous fistulas (AVFs) and outlines a handful of novel solutions on the horizon.

I

n 2017, about 750,000 US patients were diagnosed with end-stage kidney disease (ESKD), with a rising yearly incidence of 3%. Some 87% of these patients will require renal replacement therapy with haemodialysis. The Kidney Disease Outcomes Quality Initiative (KDOQI) recommends an autogenous AVF as the preferred vascular access for haemodialysis.

However, AVFs have a one-year patency of around 62%, requiring frequent percutaneous transluminal angioplasty (PTA) procedures, which cost more than US$4 billion per year. Of the roughly 200,000 PTAs performed, about 50% will fail at six months due to development of venous stenosis and neointimal hyperplasia causing reduced blood flow and suboptimal haemodialysis.

The pathophysiology and molecular mechanisms of venous stenosis and neointimal hyperplasia after AVF creation are not yet fully understood and have been extrapolated from other vascular injuries, such as arterial stenosis formation. To date, there are no therapies that have been approved that reduce these formations.

Histologic examination of experimental and clinical specimens from failed haemodialysis vascular access shows that there is increased proliferation with the pres-

ence of inflammatory and smooth muscle cells accompanied with collagen matrix deposition leading to fibrosis and venous stenosis formation1. This is similar to other vascular injuries, including arterial stenoSanjay Misra sis and venous conduits in lower-extremity occlusive arterial disease.

Many therapies have been tested in arterial systems and then translated to the dialysis vascular access. One weakness of this approach is that, initially, patients who were not on dialysis were excluded from these studies2–4.

Moreover, when dialysis is an independent risk factor for restenosis in all vascular beds. Therefore, it is important to test therapies for dialysis vascular access in preclinical models prior to embarking on large clinical studies.

There are new, exciting novel local therapies on the horizon that have been tested in preclinical animal models, including the rodent and the pig5. One of these is 1alpha,25-dihydroxyvitamin D3 (1,25[OH]2D3)—which is active Vitamin D3—used in patients with chronic kidney disease (CKD) for calcium homeostasis. Our lab encapsulated it in polylactic-co-glycolic acid (PLGA) nanoparticles loaded in Pluronic F127 hydrogel (1,25 nanoparticles [NPs]).

Using male C57BL/6J mice and pigs with CKD, that periadventitial delivery of 1,25 NPs to the stenotic vein after PTA reduced venous stenosis/neointimal hyperplasia.

Twenty-one days after PTA, 1,25 NP-treated vessels had increased lumen vessel area, with decreased neointima

Consistent use of VasQ device demonstrates “excellent” outcomes in radiocephalic fistula creation The VasQ device (Laminate Medical Technologies) appears to be a “suitable aid” in the creation of functional radiocephalic arteriovenous fistulas (AVFs). This was the concluding finding of a study in which the implantable device— an external anastomotic support system—was associated with high AVF maturation and cannulation rates.

WRITING IN SEMINARS IN DIALYSIS, Robert Shahverdyan (Asklepios Klinik Barmbek, Hamburg, Germany) and colleagues note: “The routine use of the VasQ external support for forearm radiocephalic AVF creation resulted in high unassisted maturation rates with long-term durability of the access. It has resulted in a 95% success rate of physiologic AVF maturation, with 86% of unassisted maturation after four weeks and secondary patency rates of forearm VasQ radiocephalic AVFs of 84% at 36 months.

“These outcomes compare very favourably to previously published studies reporting outcomes of forearm AVFs and are similar in secondary patency to recent reports from dedicated centres—but with lower rates of intervention to achieve maturation.”

In an effort to overcome some of the more prominent drawbacks relating to May 2022 – Issue 3

AVFs, and in particular forearm radiocephalic fistulas—including low maturation rates, significant early thrombosis, and the fact it often takes several months before cannulations can be attempted—the researchers have adopted the routine use of VasQ at their centre in Germany. And, in light of a number of recent studies of the device in both upper-arm brachiocephalic AVFs as well as radiocephalic AVFs, which generated largely positive results regarding fistula outcomes, they expanded the use of VasQ for all radiocephalic AVFs in the hospital and retrospectively evaluated prospective data from patients implanted with the device between June 2018 and August 2021. The patient cohort was followed up for up to 36 months, Shahverdyan and colleagues detail.

Across the study period, the VasQ device was used to create 150 radiocephalic AVFs in a total of 148 patients. The study cohort was predominantly male (68%), with a median age of 64 years (range=28–87 years), and the most prevalent comorbidities included arterial hypertension (72%) and diabetes (45%). Some 58% of patients were receiving dialysis treatment due to end-stage kidney disease at the time of access creation as well.

Regarding physiological AVF maturation, the researchers note that this was achieved in 95% of patients (142/150),

area/media area ratio, and a reduction in inflammatory cells, fibrosis, and proliferation6.

Moreover, periadventitial delivery of 1,25 NPs to the stenotic vein after PTA in an experimental model of rodents reduces venous stenosis/neointimal hyperplasia too.

Another one of these technologies is local delivery of nitric oxide-releasing gel aimed at reducing venous stenosis formation7. First-in-human studies are being planned with these technologies.

References: 1. Brahmbhatt A, Remuzzi A, Franzoni M, et al. The molecular mechanisms of hemodialysis vascular access failure. Kidney Int. 2016; 89(2): 303–16.

2. Rocha-Singh K J, Duval S, Jaff M R, et al. Mortality and Paclitaxel-Coated Devices: An Individual Patient Data Meta-Analysis. Circulation. 2020; 141(23): 1859–69.

3. Selzman C H, Miller S A, Zimmerman M A, et al. Monocyte chemotactic protein-1 directly induces human vascular smooth muscle proliferation. Am J Physiol Heart Circ Physiol. 2002; 283(4): H1455–61.

4. Dake M D, Ansel G M, Jaff M R, et al. Durable Clinical Effectiveness With Paclitaxel-Eluting Stents in the Femoropopliteal Artery: 5-Year Results of the Zilver PTX Randomized Trial. Circulation. 2016; 133(15): 1472–83; discussion 83.

5. Singh A K, Cai C, Kilari S, et al. 1alpha,25-Dihydroxyvitamin D3 Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas. J Am Soc Nephrol.

2021; 32(4): 866–85.

6. Cai C, Kilari S, Zhao C, et al. Adventitial delivery of nanoparticles encapsulated with 1alpha, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model. Sci Rep. 2021; 11(1): 4772.

7. Somarathna M, Hwang P T, Millican R C, et al. Nitric oxide releasing nanomatrix gel treatment inhibits venous intimal hyperplasia and improves vascular remodeling in a rodent arteriovenous fistula.

Biomaterials. 2022; 280: 121254.

SANJAY MISRA is a professor of radiology in the Department of Radiology at the Mayo Clinic in Rochester, USA. The author declared no relevant disclosures.

while the remaining 5% (8/150) failed before maturation and were abandoned.

Seven of those failures were converted to another access type, and one patient died prior to planned arteriovenous graft (AVG) creation. Unassisted maturation was observed in 89% (133/150) of all cases, with 86% (129/150) achieving maturation four weeks after access creation.

And, from the remaining nine primarily nonmatured AVFs, eight patients achieved successful balloon-assisted maturation within 165 days.

Discussing AVF cannulation outcomes, Shahverdyan and colleagues state that the number of accesses reaching a dialysis status or starting apheresis at the end of the retrospective review window was 81.3% (122/150). One patient continued peritoneal dialysis despite having a matured fistula, based on a personal decision, leaving 121 cases with active dialysis access use. Two-needle cannulation was achieved in 90% (n=109) of these patients, while radiocephalic AVF failure

Robert Shahverdyan

occurred in 6.6% (n=8), leading to a functional patency rate of 93.4%. The authors go on to report that the median time to first successful cannulation for 74 of the 87 patients who were on active haemodialysis prior to AVF creation (85%) was 41 days.

At six, 12, 18, 24 and 30 months, rates of assisted patency (time from AVF creation until an AVF occlusion, which was successfully restored) were 89%, 81%, 78%, 73%, and 73%, respectively, and secondary patency rates of 94%, 87%, 86%, 84%, and 84%, were observed too. Shahverdyan and colleagues further state that 63% of AVFs (94/150) were free from further interventions, with the remaining 37% (56/150) undergoing a total 102 interventions throughout the study period. As such, the number of interventions per patient year was 0.55. Ninety-eight percent of all interventions were successful, with the vast majority (97%) involving a percutaneous transluminal balloon angioplasty.

Finally, touching on safety outcomes, the researchers relay that the study achieved a 100% technical success rate on device implantation as planned, and no device-related adverse events were recorded. In addition, no patients developed symptomatic haemodialysis access-induced distal ischaemia or high-flow AVFs (Qa≥2l/min) during the study period.

“Routine use of the VasQ external support device during forearm radiocephalic AVF creation is associated with low primary failure rate, high and early physiological maturation, and low rate of intervention to achieve physiological maturation and usability,” Shahverdyan and colleagues conclude.

Vein Preservation

Ultrasound technology “integral” to renal replacement therapy planning and delivery CX 2022

Jennifer Hanko (Belfast City Hospital, Belfast, UK) used the case illustration of a 48-year-old female to deliver her presentation on ‘Mapping for all options’ as part of the Vascular Access Masterclass at this year’s Charing Cross Symposium (CX 2022; 26–28 April, London, UK). In detailing the various stages of renal replacement therapy at which ultrasound was utilised, Hanko demonstrated the extent to which this technology is beneficial for the patient and the medical professional.

W

hen the patient was first seen, she presented with what appeared to be “rapidly declining kidney function”, as described by Hanko.

Ultrasound showed options for a mid-forearm radiocephalic fistula and a left brachiocephalic fistula, and she was advised to preserve her left arm veins. Hanko also noted that managing her blood pressure and urinary tract infections slowed progression, but that her kidney function continued to decline nonetheless.

Due to previous abdominal surgeries and an ileal conduit, Hanko explained, the patient was not suitable for peritoneal dialysis. She was added to the deceased donor transplant list, in the absence of live donor options.

The patient was suspended on-call for kidney transplant due to a retrosternal goitre with tracheal deviation that required surgery. Hanko reported that, at this stage, she proceeded to a fistula creation in the left brachiocephalic vein. The cephalic vein diameter on ultrasound was 2.7mm. Yet, upon surgical exploration, the vein was found to branch and turned out to be only 2mm in diameter.

Hanko described the result of the surgical process: a “difficult arteriovenous anastomosis [that achieved] some distention of the vein, [although no] pronounced thrill”.

She recalled that ultrasound assessment on the day of

fistula creation did show low flow through the fistula, but there were concerns it would not mature adequately.

At one-month follow-up, Hanko recounted, the fistula maturation was seen to be “[inadequate]”, and the patient underwent angioplasty to the perianastomotic area four weeks later to treat the 1mm stenosis present. According to Hanko, the radiologist reported that ‘a wire and catheter were inserted through the cephalic vein into the brachial artery with eventual success, in spite of the vein’s tortuosity’. There were “no complications at the time” of the procedure, and a final fistulogram displayed improved appearances.

Hanko then proceeded to report on the results of ultrasound at the patient’s next follow-up. There had been circumferential, upper-arm bruising and, on ultrasound, evidence of a perianastomotic haematoma, but there was no longer active bleeding. Three weeks later, the patient

Jennifer Hanko

required stent grafts for an expanding pseudoaneurysm at her elbow, which limited the fistula’s cannulation zone. A solution was found, Hanko relayed: single-needle, extended-hours, at-home haemodialysis through the fistula.

At further follow-up later the same year, the patient underwent a left lobe thyroidectomy and was relisted for a kidney transplant. However, four months later, in January 2022, the fistula thrombosed. Hanko described the vein as being too “tortuous” and “immature” to salvage, so the next step was to completely reassess access options.

Hanko informed the audience that the brachial artery, which had matured to 6mm, plus a good axillary vein, was suitable for a rapid-stick brachioaxillary (BA) graft.

Two months after BA graft insertion, the brachial artery had increased in size by 0.9mm, and flow through it was 2,240ml per minute.

Currently, the plan for this patient is home haemodialysis via the left brachioaxillary graft until a deceased donor kidney transplant becomes available. The good vascular access and plan for extended-hours home haemodialysis have “[taken] the pressure off ” finding a donor, Hanko stated, meaning only a “good-quality kidney” would now be considered for transplant, as the operation may be more challenging due to the number of previous abdominal surgeries. Hanko concluded her summary of the case by underlining all the stages in the patient’s care at which ultrasound mapping proved an asset: guiding vein preservation, choosing the modality, creating access, needling access and for access follow-up.

In a discussion following her presentation, Hanko added: “This is one of my most challenging recent cases and I thought it was interesting to present because, in retrospect, there are a lot of things we might have done differently—but this is the reality of looking after patients with complex disease and complex workup for renal replacement therapy. Always having a backup plan is key too because, despite our best plans, things do not always work out.”

“Always having a backup plan is key too because, despite our best plans, things do not always work out.”

Save Your Vein: Transforming venous preservation from hope into reality Jeremy Crane (London, UK) discusses the topic of vein preservation—including its central importance to successful dialysis access creation, and practical measures for achieving it in a clinical setting.

THE PRESENCE OF PATENT PERIPHERAL key veins in the arm is an obvious central tenet underpinning the creation of a successful arteriovenous fistula (AVF) for dialysis—the gold-standard form of vascular access. A well-functioning AVF allows for a durable vascular access, associated with reduced infection risk and mortality compared with central venous catheters, translating into a superior long-term outcome for a dialysis patient. Paradoxically, preserving these key veins (vein preservation) is practiced poorly in many renal failure programmes.

In this context, what is vein preservation? It is the practice of avoiding blood tests and indiscriminate insertion of intravenous (IV) lines into key veins in the arms—the anterior elbow crease and the cephalic vein at the lateral wrist—that are fundamental in creating an AVF. Repeated venepuncture and IV-line insertion has the potential to injure veins and render them useless for AVF creation by causing thrombosis, stenosis and phlebitis. It stands to reason that a practical and effective vein preservation policy

is integral in the management of all patients with kidney disease.

Effective implementation of such a policy can be a major contributing factor in improving incidence Jeremy Crane and prevalence of the gold standard AVF in haemodialysis programmes across the board.

A concise guideline that can be shared with healthcare professionals and patients for them to practice simple and effective vein preservation is as follows: 1. Always take blood from the back of the hand whenever possible 2. If the back of the hand is not an option, the elbow crease can be used, but rotate arms 3. After examination of the arm veins, a specific directive can be given to inform which arm needs to be preserved 4. Avoid unnecessary or duplicate blood tests One initiative to improve vein preservation knowledge and practice at a large, UK-based healthcare organisation is the “Save Your Vein” campaign. To summarise initial results of the campaign, a baseline assessment of knowledge and practice of vein preservation for both patients and healthcare professionals was carried out before and after an awareness campaign.

This initial survey demonstrated only 31.5% of

9

Vein preservation recommendations:

Always take blood from the back of the hand whenever possible If the back of the hand is not an option, the elbow crease can be used, but rotate arms After examination of the arm veins, a specific directive can be given to inform which arm needs to be preserved Avoid unnecessary or duplicate blood tests

patients and 3% of healthcare staff were aware of the concept of vein preservation.

On this basis, the second phase of the campaign was implemented in 10 renal units.

Approximately 2,000 patients and healthcare staff were involved. Patients were issued alert cards and leaflets, while staff were given lanyards and attended teaching sessions. Posters were placed in key healthcare areas. A post-intervention survey performed three months after the baseline assessment showed a marked improvement in knowledge, with 94% of patients and 92% of staff showing awareness of vein preservation.

What was demonstrated was that the ‘Save Your Vein’ campaign was highly effective in increasing knowledge and awareness amongst patients and healthcare groups. It also resulted in improved practice and adherence to best practice guidelines, and was well-received by those involved and other stakeholder groups. With this validation, the campaign was incorporated into the 2019 Kidney Disease Outcomes Quality Initiative (KDOQI) guideline update and there is a website solely dedicated to vein preservation for patients with kidney disease.

JEREMY CRANE is a consultant transplant and vascular surgeon at Imperial College Healthcare NHS Trust in London, UK. His practice involves kidney and pancreas transplantation, and he is the lead for vascular access surgery, having set up the vascular access surgical programme for West London.

The author declared no relevant disclosures.

Issue 3 – May 2022

10

Cardiovascular Outcomes

Precision banding offers “effective, low-morbidity approach” in high-flow haemodialysis accesses A retrospective review involving nearly 300 patients has concluded that precision banding as a treatment for high-flow haemodialysis accesses offers “an effective, low-morbidity approach”. The findings of the review are published in the Journal of Vascular Access ( JVA).

retrospective review of a prospectively maintained clinical database in order to capture patients undergoing precision banding within a single tertiary care institution between 2010 and 2019. Multivariable logistic regression modelling was used to assess the review’s primary outcome measures, access circuit thrombosis within 30 days and banding failure (defined as re-banding his study represents the largest series within one year of the index banding procedure). of precision banding for high-flow The researchers found that, in total, 297 haemodialysis accesses, and high- patients underwent banding during the study lights the safety and versatility of the procedure,” period for a total number of 398 encounters.

Rebecca Scully (Brigham and Women’s Hospi- The median follow-up time was 157 (52–373) tal, Boston, USA) and colleagues write in JVA. days, they note in their JVA report. Most arte“High-flow accesses were successfully riovenous fistula (AVF) accesses banded in both symptomatic patients (84%) were in the upper arm of the presenting with ischaemic steal, patient with brachial artery inflow heart failure or pulmonary hypertenand half of the banding procedures sion, and aneurysmal degeneration were performed for flow imbalance as well as at-risk patients with flow based on examination, duplex ultraimbalance.” sound, or a fistulogram. In addition, The authors begin their report by the median, intraoperative, pre-bandnoting that high-flow haemodialysis Rebecca Scully ing flow volume—based on intraoperaccesses are a well-recognised source ative thermal dilution—was 1,545ml/ of patient morbidity. They also claim that, min, which was reduced to 640ml/min followamong available management strategies, inflow ing access banding. This represented a median constriction based on real-time physiologic reduction in flow rate of 58%. flow monitoring offers a “technically straightIn terms of primary outcome measures, Scully forward, data-driven approach with poten- and colleagues report that the 30-day thrombosis tially low morbidity”—but large, contemporary rate after banding was 3.8% (15/397) with a total series examining it are lacking, in spite of the thrombosis rate of 6.5% (26/368) throughout the benefits offered. entire study period and a median time to event of As such, Scully and colleagues undertook a 5.5 (2–102) days. Multivariate analysis for 30-day

“T

30-day thrombosis rate after banding:

3.8% Total thrombosis rate:

6.5% Re-banding rate within one year:

13.6% Total re-banding rate:

26%

CX 2022 Understanding cardiac status is key

in optimising vascular access

“PATIENTS WITH RENAL FAILURE, AND IN particular end-stage renal failure, have an excessive rate of cardiovascular events and mortality,” Joris Rotmans (Leiden University Medical Center, Leiden, The Netherlands) told attendees of the Vascular Access Masterclass at the 2022 Charing Cross (CX) Symposium (26–28 April, London, UK) in a presentation looking at vascular access creation and the heart.

“A 30-year-old dialysis patient has a cardiovascular mortality that is similar to an 85-year-old with a normal kidney function,” detailed Rotmans, making the case as to why understanding a patient’s cardiovascular status is fundamental to selecting the right type of access.

Rotmans’ presentation touched upon relative preoperative considerations, and focused on patients’ “more systemic” aspects, including patient prognoses, cardiac status and finger pressure.

Focusing on patient prognosis, Rotmans offered two prediction models that he said are important to take into consideration. The first, developed by Emmanuelle Dusseux (Centre Hospitalier Universitaire de Nice, Nice, France) and colleagues, focuses on cardiovascular status and scores patients based upon their characteristics.

Those with the highest score have a prognosis of 50% at one year. The second prognosis tool—developed by Lewis Cohen (Baystate Medical Center, Springfield, USA) et al—is available online and projects six-month survival for patients who receive haemodialysis.

May 2022 – Issue 3

Returning to the relationship between cardiac function and the heart, Rotmans explained that the link is multifactorial “[…] on the one hand, because of hypertension leading to hypertrophy, but also the access itself, due to the additional cardiac output that needs to be generated resulting in hypertrophy”.

Dialysis creates a clearance of around 10ml per minute, he added, meaning that the uremic toxins that cause progressive atherosclerosis and the dialysis procedure itself can contribute to heart rhythm disorders and heart failure.

Turning to catheter-related mortality, Rotmans explained that patients with catheters have a higher mortality compared to patients with a fistula. “It is good to realise that the excess mortality of patients with catheters is not directly related to the access itself, because the access-related mortality itself is very low—in the order of 2–5%,” he noted.

Rotmans then offered data from Robert Brown (Harvard Medical School, Boston, USA) et al, comparing the use of a fistula after a failed arteriovenous fistula (AVF) attempt.

The data show that, in

thrombosis identified no risk factors for thrombosis including access type, indication for banding, and banding diameter.

Regarding banding failure, the authors relay that the re-banding rate within one year was 13.6% (54/398) with a median time to re-banding of 133 (56–224) days. During the entire study period, 26% of patients (76/297) needed to be re-banded at any time. Multivariate logistic regression analysis here revealed that having a forearm radiocephalic AVF—compared to all other access types—was protective against need for re-banding at one year, as was flow imbalance as an indication for banding.

“This work highlights the safety and efficacy of precision banding for both symptomatic and asymptomatic access patients with high-flow volume,” Scully and colleagues write.

“There are limitations to the study. First, this is a single-centre, retrospective review performed at a high-volume teaching institution with a multidisciplinary team dedicated to haemodialysis access and maintenance. We recognise that these types of resources and clinical experience may not be available to all proceduralists and may not be generalised to other US centres. The retrospective nature infers that the findings are associative.”

In addition to noting the “excellent symptomatic relief ” offered by precision banding in high-flow haemodialysis accesses, the authors conclude by stating that early thrombosis is a rare event, and that—in the long term—one in four patients may require re-banding to control flow volumes.

“This study represents the largest series of precision banding for high-flow haemodialysis accesses, and highlights the safety and versatility of the procedure.”

patients who develop non-maturation, mortality rate is quite similar compared to patients that utilise an AVF for dialysis, he explained, suggesting that it is not the catheter itself, but rather the patient factors that are responsible for this finding. ”I am not advocating that we should give catheters or grafts to everyone,” he commented, adding: “In the patients that are very vulnerable, with a poor prognosis and a poor cardiac status, alternatives to AVFs are a good consideration.”

Furthermore, digital plethysmography—measuring finger pressure—could be a useful tool to predict the risk of haemodialysis-induced distal ischaemia (HAIDI), Rotmans explained, commenting “[...] that is a useful thing to do before access surgery to avoid that complication that might need immediate intervention”.

Summarising his core messages, Rotmans told CX attendees that they should take the patient prognoses into consideration, adding that “[…] one size does not fit all, so [it is] not a fistula for all patients, at least in my opinion.”

Cardiac evaluation is fundamental in patients with cardiac history or symptoms of heart failure, he said, as is avoiding high-flow fistulas in patients with advanced heart failure.

Joris Rotmans

Advertorial

11

This advertorial is sponsored by Vascular Therapies

Sirogen : A potential solution for improving arteriovenous fistula maturation TM

Arteriovenous fistula (AVF) maturation is a pivotal event in patients requiring haemodialysis. Maximising the number of fistulas that mature, become suitable for initial clinical use and remain suitable for sustained clinical use continues to be a high-priority objective in vascular access. To improve maturation success, an unmet medical need, Vascular Therapies is developing the sirolimus-eluting collagen implant SirogenTM, a single-dose prophylactic delivered intraoperatively at the time of the index AVF surgery.

Sirogen will be tested in ACCESS 2, an upcoming phase 3 randomised clinical trial in high-risk patients.

A

t the recently concluded Charing Cross Sympo- ing coronary stents. In comparison to paclitaxel, a cytosium (CX 2022; 26–28 April, London, UK), toxic antiproliferative with a very narrow margin of renal transplant and access surgeon Rajesh safety (which, if breeched, can result in vascular necroSivaprakasam (Barts Health NHS Trust, London, UK) sis), sirolimus is a cytostatic with a wide therapeutic presented results from ACCESS—a multicentre, prospec- window and negligible vascular toxicity. tive, randomised controlled trial that enrolled 269 patients with end-stage kidney disease (ESKD) and Is there any risk of systemic immunosuppression? chronic kidney disease (CKD) from 20 US sites. The study Iyer: For therapeutic immunosuppression, an oral was designed to evaluate the safety and effectiveness of dose between 2–5mg per day of sirolimus is required to Sirogen to improve outcomes in patients undergoing achieve and maintain a target whole-blood trough level surgical creation of an AVF for haemodialysis. of 15ng/ml (range 12–20ng/ml). In contrast, the one-time The trial did not meet its prespecified dose of sirolimus delivered perivascularly to endpoints. Analysis of patient-level data the vessel wall from the Sirogen implant is showed that, despite randomisation, the a fraction of the oral dose and pharmacokitreatment group had a significantly higher netic data show that a very small amount of proportion of patients aged 65 years and older the locally eluted sirolimus gains access to the and those with coronary artery disease (CAD). circulation, resulting in systemic concentraBoth variables are known risks for fistula tions that are well below levels required for maturation and this imbalance biased trial Sriram Iyer immunosuppression. outcomes in favour of the controls.

To understand the impact of this imbalHow does a drug delivered from outside ance, a post hoc analysis of the risk-differentithe blood vessel reduce stenosis that is ated data using an age cut-off of 65 years was inside the vessel? performed. In high-risk ESKD patients, the Iyer: Research using an animal arteriovenous Sirogen group showed a significant improvegraft (AVG) anastomosis model has shown ment in fistula maturation. This benefit was that, soon after anastomosis is completed, durable; at 12 months, a higher proportion adventitial fibroblasts begin to proliferate, of Sirogen-treated fistulas were functionally Surendra Shenoy acquire the phenotype of myofibroblasts (i.e. patent with freedom from abandonments express smooth muscle cell actin), migrate (better secondary patency). To confirm through the media to the intima and are major these results, Vascular Therapies is initiating contributors to the final neointimal tissue ACCESS 2, a randomised trial for high-risk volume in the peri-anastomotic area. This ESKD patients. explains how periadventitial application of Here, Sivaprakasam is joined by Vascular Sirogen, a formulation that contains the antiTherapies founder and chief scientific officer proliferative sirolimus, has the potential to Sriram Iyer, and fellow renal transplant and Rajesh Sivaprakasam reduce the risk of an intravascular stenosis access surgeon Surendra Shenoy (Washington (‘outside-in’ approach).

University School of Medicine, St Louis, USA), in discussing Sirogen, and the ACCESS and ACCESS 2 studies.

What are the most interesting findings from your CX 2022 presentation of ACCESS? Why sirolimus?

Sivaprakasam: The ACCESS randomised trial confirms Iyer: Sirolimus (the active drug in Sirogen) has been advancing age is a risk factor for AVF maturation as proven to provide clinically beneficial anti-inflamma- shown by other published studies. Local targeted drug tory and antiproliferative effects. Vascular injury, such as delivery using the perivascular approach is feasible and the trauma related to the surgical creation of a vascular there were no safety concerns. In the ≥65-year-old highanastomosis, stimulates the normally quiescent cells in risk ESKD cohort, Sirogen use provided a strong effithe vascular wall to enter a proliferative phase marked cacy signal for improving AVF maturation. The benefit by secretion of extracellular matrix, proteases, growth appears to be therapeutically durable as evidenced by factors and cytokines, and migration to the intima. the better 12-month functional and secondary patency Although cell migration and proliferation are important in comparison to the standard of care controls. and expected biological responses to vessel injury, this process is largely uncontrolled and unpredictable, and Since the high-risk subgroup analysis from ACCESS an excessive proliferative response results in neointimal is post hoc, how do you know the results are not a hyperplasia, leading to a flow-limiting stenosis. false positive?

Sirolimus combines with the mechanistic target of Sivaprakasam: As with any post hoc analysis, it is entirely rapamycin (mTOR) and suppresses cell proliferation. possible that the results in the ≥65-year-old group are Clinical proof to support the antiproliferative action false positive; validation awaits the completion of comes from the extensive experience of sirolimus-elut- the high-risk ACCESS 2 trial. However, optimism that

these encouraging results will be confirmed is based on outcomes using Sirogen in other patient groups. To date, across three different cohorts, patients treated with Sirogen have outperformed historical benchmarks.

These studies include: • The maturation success of Sirogen-treated AVFs in the phase 2 AVF study (n=30) • The open-label cohort from the phase 3 study (n=26) • The outcomes in the high-risk randomised cohort of the ACCESS study This consistency provides reassurance that the results are likely ‘real’, and not a one-off or false positive.

The ACCESS 2 study will only include patients aged 65 years and older—why is this?

Shenoy: ACCESS 2 is designed to be a high-risk trial, to help validate the results from the ACCESS study.

Although advancing age is a risk for fistula non-maturation, this does not mean that patients younger than 65 years do not require treatment to help improve maturation of their AVFs. Approximately one in three AVFs in patients younger than 65 years have problems with maturation and fistula outcomes in younger patients also need improvement.

Why is enrolment in ACCESS 2 restricted to radiocephalic AVFs? Shenoy: High-risk variables that influence fistula maturation include advancing age, female gender, African American ethnicity, comorbidities like diabetes mellitus, and presence of CAD and peripheral arterial disease.

Because vessels in the forearm are smaller, maturation outcomes of radiocephalic fistulas are inferior to those in the upper arm. In the USA, over the last 25 years, maturation problems have led to a 50% reduction in the placement of forearm radiocephalic fistulas. Whereas, in the late 1990s, almost 70% of AVFs were radiocephalic, more recent data suggest that only about 35% of fistulas are created in the radiocephalic location. If the ACCESS 2 trial results confirm the maturation benefit for radiocephalic AVFs, it will be a clinically important outcome, because it will help increase the number of access sites for patients.

Are there other potential indications for Sirogen?

Shenoy: Testing the value of Sirogen delivered locally at the venous anastomosis of polytetrafluoroethylene (PTFE) AVGs is the next logical indication. A small phase 2 AVG feasibility study performed by Vascular Therapies showed a one-year primary patency rate of 76% for sirolimus-treated access grafts. Of course, these results now need to be reproduced in a larger patient cohort.

Another possible indication includes improving the patency of below-knee bypass grafts in patients with critical limb-threatening ischaemia, because flow-limiting stenosis at the vascular anastomosis site is an important cause of graft occlusion and failure.

Sirogen product illustration

Venous Component Vein

Anastomosis Component Artery

Issue 3 – May 2022

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Profile

Q&A

Matteo Tozzi Having grown up and studied medicine in Rome, Matteo Tozzi is currently deputy head of the Department of Medicine and Surgery, and associate professor of vascular surgery, at the University of Insubria in Varese, Italy. His work within the vascular access field has led to his involvement in numerous significant research endeavours over the past decade, including as a leading investigator for the Lutonix Global AV Registry (BD), the multicentre TreSTAR registry and, most recently, a first-in-human study evaluating the Axess haemodialysis access graft (Xeltis). Here, Tozzi discusses his career so far, and provides perspectives on exciting developments and unmet needs in vascular access care, with Renal Interventions.

What initially attracted you to medicine, and the fields of vascular surgery and vascular access in particular?

The hands-on nature of vascular surgery required to reconstruct conduits, like a plumber, and the myriad of treatments possible from peripheral arteries to central veins, fascinated me from the very beginning, during my first years of medical school. In 2006, I started my career in kidney transplant surgery, and the transition to vascular access surgery shortly followed this. Since then, I have been passionate about this chapter of surgery and its evolution, based on technique, haemodynamics, and technology. The creation and maintenance of vascular access is fundamental to the life of the end-stage kidney disease (ESKD) patient; the satisfaction you get from participating in this process is high. This is the dream that I am always trying to achieve.

Who have your mentors been and how have they impacted your career?

I have had many mentors and each of them has inspired me during my surgical journey.

Certainly, Patrizio Castelli has been the mentor who has allowed me to develop and cultivate my interests in the field of vascular surgery. I have him to thank for my involvement in kidney transplant surgery and then in vascular access surgery as well. Surgery is based on a continuous evolution and this characteristic is founded on mentors capable of teaching the passion for this discipline.

May 2022 – Issue 3

What do you feel has been the most important development in the field of vascular access surgery during your career?

I believe that the development of early-cannulation graft technology has been one of the biggest developments. If I think about my efforts in the area of vascular access, early cannulation has enabled us to treat more patients with no vessel fit for native access. This contrasts with the constant increase of central venous catheters (CVC) and the dependence on these devices, which will continue into the future.

Patients requiring kidney replacement therapy are increasingly elderly and arrive at dialysis after long treatments that often deteriorate the vasculature. The construction of vascular accesses is therefore more and more complex.

The study of the chosen surgical technique to create functional grafts with the lowest possible rate of complications, and the study of the most effective maintenance between drug-coated balloons (DCBs) and stent grafts, has filled these last 15 years of my career.

In light of the various clinical data that have emerged in recent years, how would you assess the current landscape regarding DCBs and dialysis access?

The pathophysiology of intimal hyperplasia is one of the bases for understanding the high rate of reinterventions that our accesses require.

Multifactorial genesis makes its treatment complex, but the advent of DCBs is definitely a

milestone for the treatment of vascular access stenosis. After the storm that hit antiproliferative therapy, surrounding paclitaxel, we now have more knowledge about its safety.

At least two randomised trials now give us a level of evidence of superiority in their use for treatment, with a reduction in the number of treatments to maintain circuit patency and a statistically significant target-lesion primary patency (TLPP) compared to treatment with simple angioplasty. It is now time to consistently use them as a first-line treatment. We are also currently conducting a study of paclitaxel measurement in the blood of patients undergoing DCB treatment—evaluated by high-pressure liquid chromatography (HPLC). The preliminary results are very interesting and I hope the publication will finally put an eternal end to doubts of paclitaxel-induced complications.

As guidelines shift from ‘fistula first’ towards simply ‘the right access’, what do you think is the future role of arteriovenous grafts?

The arteriovenous graft (AVG) has two important applications in the world of vascular access today: in patients with vessels not suitable for native vascular access creation, and in patients with a high risk of maturation failure. Prosthetic access in these patients reduces morbidity and is more cost-effective than the use of a CVC. Today, grafts are a resource to be cultivated to reduce CVC dependence for those patients with poor vasculature. Often, in these patients, it is possible to take advantage of the maturation of the venous outflow and, the second time around, perform a shift to native access; this bridge-to-native modality is my favourite with early-cannulation grafts.

The early-cannulation graft often helps me to create an access without having to use CVCs in young crashlanders.

How has the COVID-19 pandemic impacted dialysis patients requiring vascular access care—in Italy, but also across Europe more broadly?

The COVID-19 pandemic has created enormous problems for haemodialysis patients, with a major increase in morbidity and mortality.

Varese, the city where I work, has been affected severely by COVID-19, and hospital activity has changed consequently. The reduced possibility of creating vascular accesses and of managing the associated complications has increased the rate of thrombosis and access abandonment, and has increased the percentage of CVCs being used too. An important factor during the upcoming waves of the pandemic are the endovascular methods that could help us in increasing native fistulas. I believe that, today, our responsibility is to reverse this trend by utilising all of the available new technologies and harnessing everyone’s dedication to recover the lost time.

What is the most interesting piece of research in vascular access surgery you have seen over the past year?

The development and the beginning of the use of prostheses based on a futuristic process called endogenous tissue restoration (ETR)—a synthetic matrix that, once implanted in humans, can degrade and be replaced by living tissue created from the patient’s own cells—definitely represents my main interest over the past year. The ability to reduce some typical graft complications, such as infection or cannulation depletion rates, by this process will be critical for our patients in the future. They will be the beneficiaries of futuristic prostheses that combine the benefits of synthetic grafts with those of native vessels.

Fact file Current appointments: 2006–present: Clinical lecturer of Vascular Surgery, University of Insubria, Varese, Italy 2014–present: Associate professor of Vascular Surgery, University of Insubria 2022–present: Deputy head, Department of Medicine and Surgery, University of Insubria

Education: 2001: Degree in Medicine and Surgery, University “La Sapienza” of Rome, Italy 2006: Specialisation in Vascular Surgery, University of Insubria 2020: National Scientific Qualification of professor of Vascular Surgery, Abilitazione Scientifica Nazionale (ASN)

Honours (selected): 2017: Member of council board, Vascular Access Society (VAS) 2020: Principal investigator, TreSTAR registry 2021: Principal investigator at study site, first-in-human Axess study Member, Società Italiana di Chirurgia Vascolare ed Endovascolare (SICVE) Reviewer, International Journal of Surgery, Journal of Nephrology, and Journal of Vascular Access (JVA)

Illustration by: Andy Watt / NB Illustration

Profile

What is the most significant unmet need within the wider kidney care field right now?

I believe that effective treatment of diabetic nephropathy is sorely lacking in the chronic kidney disease (CKD) landscape today. Diabetes represents an emergency in the Western world and, with it, the worst complications it causes: the diabetic foot and nephropathy. To date, the prevention or treatment of complications are our only weapons and, unfortunately—with regard to kidney damage—we are defenseless.

Looking back over your career, could you describe one particularly memorable case or patient, and why it has stuck with you?

I do not think it is possible to choose one single case, as each of them has left me with something positive, and for that I thank them. Resilience and the determination to live are the best lessons that have been passed on to me. I aspire to continue this adventure with my patients and hope to have given them something positive as well.

“The pathophysiology of intimal hyperplasia is one of the bases for understanding the high rate of reinterventions that our accesses require.

Multifactorial genesis makes its treatment complex, but the advent of DCBs is definitely a milestone for the treatment of vascular access stenosis.”

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What advice would you give to people embarking on a career in the field of vascular surgery?

I think I am lucky, because I chose to be a vascular surgeon early in medical school. I believe that the desire to continue to learn and a certain spirit of sacrifice for the many hours spent in the operating room or angiography suite, in order to learn the basics, is essential. But, today, I tell students and my trainees that vascular surgery can be a very fascinating world to dive into with great satisfaction!

What are your interests outside of the field of medicine?

My main interests are mountains in all their forms. I love reading books about the history of the conquest of the 8,000 and the Seven Sisters.

My free time is dedicated to going to the mountains with my wife—accompanied by our two English bulldogs, Tea and Milly (very lazy!). Fly fishing is my other passion, as it allows me to relax completely, and I find the river water cathartic.

Issue 3 – May 2022

Kidney Patients

New National Kidney Foundation Innovation Fund seeks to accelerate kidney disease therapies THE NATIONAL KIDNEY FOUNDATION (NKF) recently announced the launch of the NKF Innovation Fund—a new impact investment programme aimed at fundamentally disrupting the fight against kidney disease.

“The kidney health landscape is broken and lacks needed innovation,” said NKF CEO Kevin Longino, a kidney transplant patient. “Dialysis has been the go-to treatment for more than half a century. Fifty years without major progress is unacceptable. About 37 million Americans have kidney disease, and many crash into kidney failure and require dialysis before ever being diagnosed. We need a fundamental change in how we deal with kidney disease. Our Innovation Fund will provide donors with a unique opportunity to see their dollars support companies pursuing the most promising therapies, treatments and prevention methods that offer the potential to transform kidney care.”

The NKF Innovation Fund’s goal is to accelerate funding, development, and commercialisation of therapies for kidney patients. It will primarily invest in early to mid-stage companies that are developing innovative, patient-centric kidney therapies, according to an NKF press release, and is modelled after similar vehicles used by other leading patient organisations to spur industry to develop transformative treatments with other diseases.

The Innovation Fund is already attracting interest from major donors and innovators, making one of its first investments in March 2022 with University of Washington (Seattle, USA) spinoff company Kuleana Technology—which is developing a portable haemodialysis device that will not require connection to an external water source. This new technology is designed to be more effective than those currently used in dialysis, allowing patients to dialyse ‘on the go’.

“Our vision is very straightforward,” added Longino. “We are going after the full spectrum of kidney disease. With the NKF Innovation Fund, we want to prevent kidney disease, eliminate the transplant waitlist, and provide better, safer treatments for dialysis patients so they can live fuller and more productive lives. That is the prism we are looking through for every investment we make, and I think our first investment into this space shows just how serious we are.”

For more information about the new NKF Innovation Fund, visit kidney.org/ innovationfund.

“We need a fundamental change in how we deal with kidney disease.”

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UK Renal Registry: Peritoneal dialysis climbs despite overall RRT decrease With comprehensive UK Renal Registry (UKRR) data from 2020 set to be published by the UK Kidney Association (UKKA) imminently, Renal Interventions previews a handful of key talking points these figures will likely trigger.

O

ne immediate observation from the 2022 UKRR report, which includes data to 31 December 2020, is that the number of new people starting renal replacement therapy (RRT) for end-stage kidney disease (ESKD) in the UK has decreased compared to previous years. RRT incidence had previously been steadily increasing for several years, but it now appears this reached a peak in 2017. Throughout 2020, 7,373 adults started RRT— an incidence of 139 per million people among adults— compared with 8,070 in 2019 and 8,069 in 2018.

A UKKA spokesperson believes that, while COVID19 likely played a part here, the exact bearing of the pandemic on these 2020 figures is not clear. They speculate that, at a time when people with long-term conditions were being advised to ‘shield’ themselves, it is likely some patients and clinicians will have tried to delay starting RRT if at all possible.

In addition, COVID-19-related mortality may have resulted in fewer patients actually reaching RRT at all.

These speculations are supported by the decrease in incidence being observed almost entirely in those aged >65 years and are borne out further by draft numbers from 2021, which indicate a recovery in RRT incidence rates.

Peritoneal dialysis and other modalities The 2022 UKRR report is also set to reveal an increase in the proportion of patients receiving peritoneal dialysis (PD) as their initial treatment modality. While the majority of UK patients (72%) still receive in-centre haemodialysis as their initial ESKD treatment, a slight jump from 20.1% to 22.1% in PD does reverse a longstanding trend that has seen its uptake as an initial treatment choice decrease over time.

The UKKA spokesperson speculates that this may have been driven by the logistical advantages and convenience offered by PD within the context of a pandemic, adding that home dialysis recommendations in the recent Getting It First Right Time (GIRFT) national report on renal medicine may help to sustain, or even build on, this increase.

UKRR data from 2020 also finds that, with a >15% increase in the proportion of incident dialysis patients starting with PD, centres in London Barts (26%) and Derby (15%) in England, and Wrexham (16%) in Wales, were among the biggest ‘improvers’ across the UK. In addition, three centres in England had a >30% prevalence of home therapies in dialysis patients in 2020: Derby (35%), Stoke (34%) and Shrewsbury (33%).

Another phenomenon revealed by the UKRR report is that the proportion of people who had a kidney transplant by day 90 decreased compared to the previous year—from 9.8% during 2019 to 7.7% during 2020. According to the UKKA spokesperson, this is almost certainly an effect of the disruption COVID-19 caused in transplant pathways.

A further observation from the report is that, from a cohort of 5,242 incident dialysis patients with data, the proportion of people initiating RRT with an arteriovenous fistula/graft (AVF/G) dropped slightly from 35.1% in 2019 to 26.8% in 2020. The UKKA spokesperson believes COVID19-related disruption to vascular access pathways may have played a role here, but notes it was likely not driven by an increase in late patient presentation, as these figures were not significantly different between 2020 and the previous year.

ESKD growth slows, AKI incidence drops Overall, the number of people treated for ESKD rose in 2020, as per UKRR data, but this increase was less substantial than in previous years. It is thought that the deaths of dialysis and transplant patients, coupled with a smaller number of new patients, resulted in these numbers increasing marginally, by 0.15% to 68,249 adults (an increase of roughly 100 people), as compared to an otherwise fairly consistent increase of 2.5% each year from 2016 to 2019—mainly led by yearly increases in the number of people with a functioning kidney transplant.

The number of acute kidney injury (AKI) episodes in England also fell during 2020, with roughly 5% fewer episodes being seen across the UKRR data. Some 10,691 episodes per million people occurred in 2020 versus 11,242 in 2019. While severe COVID-19 infection was associated with AKI, especially during the first wave of infections, there was significantly reduced National Health Service (NHS) elective activity during 2020, and the UKKA spokesperson believes this is the likely explanation for the aforementioned decline throughout the year. This speculation is supported by early indications from 2021 data that AKI episode rates increased to more than 11,000 and are approaching prepandemic levels once more.

According to the spokesperson, whether or not these trends will persist is unknown—but the latest UKRR report teaches us that timely data are critical. Throughout 2021, COVID-19 had a considerable and continuous impact on health and healthcare systems. And, in 2022—despite significantly lower rates of severe disease—many treatment pathways remain disrupted. The change in home dialysis rates, and whether this will be sustained, is of particular interest, as is the desire to understand more about the group of ESKD patients who, with their clinicians, choose not to have RRT. The weekly collection and reporting of COVID-19 infections and deaths among those on RRT was critical in influencing UK policymakers to protect ESKD patients, they state, and this has added impetus to the UKRR's shift towards more ‘real-time’ data collection coupled with a timely summary of results.

More information on this, as well as the UK Renal Data Collaboration (UKRDC), are available on the UKKA website, and the latest UKRR report will be published in full in June 2022.

About 7,500 adults started RRT in 2020 Transplant 5.9%

Home haemodialysis 0.4%

Peritoneal dialysis 22.1% In-centre haemodialysis 71.6%

Issue 3 – May 2022

16

Advertorial

This advertorial is sponsored by Alio Medical with ESKD are to lower mortality, extend renal function, and improve quality of life. In dialysed patients, preservation of residual renal function is associated with improved survival, lower morbidity and better quality of life.

The Alio SmartPatchTM: Optimising dialysis patient monitoring with a wearable, non-invasive device Owing to the various risk factors and potential complications faced by kidney disease patients undergoing dialysis treatment, new technologies that enable these patients to be monitored remotely and continuously—and ultimately managed more effectively—are a critical necessity. David Whittaker (Suburban Hospital, Bethesda, USA), Qasim Butt (Metropolitan Methodist Hospital, San Antonio, USA), Anand Patel (Providence Little Company of Mary Medical Centers, Torrance, USA) and Carole Sykes (Clinical Strategy Group, San Francisco Bay Area, USA) highlight one such innovation, the SmartPatch device, and the broad array of problems it is seeking to tackle.

T

he chronic kidney disease (CKD) patients’ complications include volume overload, hyperkalaemia, David Qasim malignant hypertension, Whittaker Butt and worsening heart failure—many of which could potentially be preventable with improved disease monitoring. In 2017, there were almost 800 million people suffering from CKD worldwide, including 39 million in the USA alone. As per a recent systematic review published in The Lancet, it is estimated to become the fifth leading cause of death globally by 2040. The natural progression of CKD is complex and involves multiple organ systems. As a result, these patients commonly present to emergency rooms (ER) 8.5 times more frequently than the general population and the prevalence of these ER visits is highest in the seven days prior to beginning dialysis.

Of all the end-stage kidney disease (ESKD) patients seen in the ER, the mean number of visits per patient year in the first, second and third years of their disease was 2.89, 2.48, and 2.54 per year, respectively, according to a population-based study. And, in another study using Medicare data, more than 131,000 of at least 11 million total ER visits were for hyperkalaemia and fluid overload in the ESKD population.

May 2022 – Issue 3

ER visits for hyperkalaemia were common in a separate population-based analysis— particularly among patients on dialyAnand Carole sis, where the condition Patel Sykes accounted for almost one half (48.8%) of all potentially preventable visits. The analysis’ researchers showed a linear trend toward developing hyperkalaemia, with the highest rates among patients with non-dialysis-dependent Stage 5 CKD (22.9; 95% confidence interval [CI], 16.7 to 29.1 ER visits per 1,000 person years) and dialysis-dependent patients (22.4; 95% CI, 17.2 to 27.5 ER visits per 1,000 person years).

Several other groups have reported that early referral to nephrology results in better control of clinical parameters, for example blood pressure and serum levels of albumin, bicarbonate, calcium, cholesterol, haemoglobin, potassium, and phosphate. This suggests that making it easier to manage a patient’s health status could reduce the likelihood of emergent complications. In a more recent study, researchers showed that patients with early referrals and frequent physician visits were less likely to be hospitalised within one year of initiating dialysis, despite these patients being older and having higher Charlson comorbidity index scores.

The primary goals for nephrologists managing patients

A wearable, patient-centred management solution In order to improve the nephrologist’s ability to optimise the overall outcomes of their ESKD population, Alio is in the process of developing an innovative device, called SmartPatch, to provide a continuous and comprehensive clinical management solution for both the nephrology team and the ESKD patient.

The Alio SmartPatch is a continuous, non-invasive, remote monitoring device that automatically sends clinically actionable data to a hub. It is worn directly over a patient’s arteriovenous fistula (AVF) or upper-extremity artery, and safely relays raw data via the hub to a cloudbased server where it is processed and analysed utilising proprietary algorithms. The server encrypts and stores the data without it being associated with a subject’s personal health information. This data collection process is invisible to the patient, who wears the SmartPatch and simply plugs the hub into a standard wall outlet in their home. There is no complex setup or configuration for the patient—the patch is worn while showering and sleeping, and typically changed at seven-day intervals.

The data collected are always accessible to the clinical team via a Health Insurance Portability and Accountability Act (HIPAA)-compliant, web-based portal and notifications can be automatically sent to a designated provider if a clinically relevant abnormality is detected.

And, in addition to recently receiving its first US Food and Drug Administration (FDA) 510(k) clearance for commercial use, Alio is undergoing multiple clinical evaluations.

The parameters being evaluated for remote monitoring in these evaluations include haemoglobin, haematocrit, potassium, oxygenation saturation, heart rate, and 10–15 seconds of audio auscultation data from flow in the underlying AVF or arteriovenous graft (AVG).

The data monitored by the SmartPatch are designed to enable improved management of the complex clinical aspects facing patients with CKD in an outpatient setting.

This improvement in monitoring and outpatient management has the goal of also boosting patient outcomes, reducing adverse events, and reducing the burdens currently faced by emergency healthcare services.

Continuous remote monitoring also provides a new level of comfort for a patient who will, for the first time, know that their critical data can be quickly, safely and remotely accessed by their healthcare team. The advantage of this degree of close monitoring is that it provides the healthcare team with the management tools it needs to proactively intervene to optimise patient outcomes.

Hyperkalaemia and hypokalaemia The kidneys play a crucial role in the regulation of potassium. Patients with CKD and ESKD are at risk of hyper/ hypokalaemia (high/low potassium levels). Hypokalaemia is typically a consequence of diuretics, while hyperkalaemia is the most common imbalance due to loss of renal function—which becomes more prevalent as the disease progresses. Hyperkalaemia has been classified somewhat arbitrarily into mild (5.1–<6mmol/l), moderate (6–<7mmol/l) and severe (≥7mmol/l). Potassium levels >7mmol/l are of critical importance as the clinical symptoms can vary widely from nonspecific muscle weakness to paraesthesias and paralysis. These high levels may also be associated with cardiac arrhythmias and sudden cardiac death. Even though electrocardiogram (ECG) changes related to hyperkalaemia are diagnostically useful, they are notoriously poor at correlating with serum potassium levels; with studies indicating accuracy in only 40–50% of chronic hyperkalaemia patients.

A further complexity in the treatment of CKD is the recommended use of renin-angiotensin-aldosterone (RAAS) inhibitors to reduce disease progression and increase survival in patients with advanced CKD (Stage ≥3), diabetes, or chronic heart failure. These recommendations are supported by several professional societies, including the European Society of Cardiology, American

Advertorial

College of Cardiology Foundation, American Heart Association and Heart Failure Society of America, as well as in the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines. The sparing of residual renal function in these patients afforded by RAAS blockade is well-accepted, but RAAS blockade is also a known risk factor for hyperkalaemia in the CKD population. Continuous, non-invasive means of remotely monitoring potassium levels in the CKD population provide the data to alter current treatment paradigms.

The management of chronic hyperkalaemia is particularly challenging. The main objective of the emergency treatment of this indication is to prevent fatal arrhythmias—which is accomplished by facilitating the movement of extracellular potassium into the cell, stabilising myocardial cell membrane potentials pharmacologically, and quickly increasing potassium elimination from the body. This is typically accomplished using insulin to drive potassium into the cell, which serves as a temporary stopgap solution, while simultaneously increasing its elimination with diuretics. However, patients with moderate/ severe renal dysfunction may need emergent haemodialysis. A subset of these patients will have chronic hyperkalaemia as a baseline that can be worsened with RAAS inhibitor administration. The objective of enduring treatment for chronic hyperkalaemia is to maintain stable serum potassium levels in the long term. If the baseline hyperkalaemia is too severe, and refractory to conservative measures (dietary modifications, diuretics, or oral potassium-binding agents), RAAS blockade may need to be stopped or reduced. Unfortunately, this leads to a loss or reduction of the benefits provided by these pharmaceuticals.

The rate of RAAS discontinuation in CKD patients is substantial. Conservative measures frequently fail because of patient intolerance to oral potassium-binding agents (resins). In one large study published by Olry de Labry Lima et al in 2021, ion-exchange resins were prescribed to 637 out of 1,499 patients receiving RAAS. Adherence to resin treatment was poor—36.8% in the first year and 17.5% by year three—and potassium levels remained elevated in most patients with severe hyperkalaemia. Two-year results from this study can be seen below.

Hyperkalaemia Mild

Moderate

Severe

RAAS discontinuation

39.8%

49.8%

51.8%

Adherence to resin treatment at two years

15.9%

29.7%

43.6%

In ESKD patients, the potential for hyperkalaemia increases as the time between dialysis sessions increases beyond 48 hours, which suggests that interventions to prevent hyperkalaemia may be more necessary when time between dialysis sessions is greater than 48 hours.

This risk occurs every week, typically over weekends, when patients are unmonitored. The rates for emergent/emergency haemodialysis have been shown to be as high as 17.6% for hyperkalaemia in a cohort of ESKD patients followed for two years. It has also been shown that the rate of emergent, first-time dialysis in worsening CKD patients can be as high as 18–19%. Unplanned dialysis sessions are associated with increased morbidity and mortality, which makes preemptive detection for unplanned dialysis important too.

The problem of anaemia Anaemia is also a very frequent complication of CKD, affecting the majority of patients with Stage 5 failure.

The anaemia creates a deficit in the delivery of oxygen to all parts of the body. Initially, the body compensates for the reduced oxygen supply by increasing the heart rate but, over time, this can lead to cardiac hypertrophy.

Deterioration of cardiac function in turn results in renal hypoperfusion that activates the sympathetic nervous system, as well as the renin angiotensin and aldosterone systems. Together, these further impair renal function. This becomes a vicious cycle known as cardiorenal anaemia syndrome (CRAS, Type IV). The syndrome can be initiated either from primary heart failure (Types I and II), primary renal failure (Types III and IV), or a combination of both (Type V). In the case of renal initiation by CKD, the predominant cause is erythropoietin deficiency, where the production of erythropoietin from the interstitial fibroblasts within the kidneys is not sufficient to meet the demand for new haemoglobin. The severity of anaemia is directly related to the degree of kidney dysfunction—the kidneys manufacture 90% of the erythropoietin produced by the body.

The most recent Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends regular assessment of haemoglobin levels in CKD patients, with increasing frequency as kidney function declines. The guidelines also recommend beginning a trial of iron therapy initially.

The target range here is 10–12g/dl in CKD patients. And, as a general recommendation, the KDIGO guidelines support the starting of erythropoiesis-stimulating agent (ESA) therapy with haemoglobin concentrations <10g/ dl (<100g/l) after assessment of all the risks associated with the therapy.

Anaemia in the CKD setting significantly increases the risk of morbidity and mortality in these patients. For coronary artery disease-related events, the ARIC study showed an increase in hazard ratio from 1.7 to 3.5 in the absence, versus the presence, of anaemia. The control of anaemia is clinically important and, if iron supplementation is not successful, then ESA therapy is warranted.

However, the dosage range and high cost of ESA drugs must be optimised based on an accurate picture of haemoglobin levels, and the target level. Unnecessarily low or high ESA dosing levels are associated with poor outcomes—as shown in the CHOIR trial. The composite primary outcome (death, congestive heart failure, stroke and myocardial infarction) was significantly higher in patients assigned to the higher haemoglobin target value of 13.5g/dl vs 11.3g/dl in this study. Establishing the correct baseline haemoglobin measurement in patients is complicated by cyclic variability, which can be affected by volume status, and the ability to remotely monitor haemoglobin levels in CKD patients would allow optimisation of the ESA therapy and may lead to improved patient outcomes.

Oxygen saturation, heart rate and auscultation The kidney is particularly vulnerable to hypoxic events.

Adequate oxygenation in patients with CKD may be impaired by a number of factors, including low haemoglobin and heart failure. Obstructive sleep apnoea (OSA) is also commonly found in patients with CKD (up to 80%) and there are currently hypotheses that the two are related. In a 2016 paper, Fahad Aziz and Kunal Chaudhary point out that OSA, CKD and hypertension are seen together as a common triad of pathologies. Therefore, OSA impacts the progression of CKD by inducing multiorgan system pathologies, such as: Cardiovascular disease effects—hypertension, arterial wall stiffness and endothelial dysfunction Respiratory

effects—direct hypoxia, which creates oxidative stress and inflammation Central

nervous system effects—sympathetic dysregulation and renin-angiotensin system (RAS) activation Not surprisingly, cardiac arrhythmias are not uncommon during hypoxic episodes. These arrhythmias may range from benign bradycardias to atrial fibrillation, and fatal ventricular tachycardias. Gami et al report in the Journal of the American College of Cardiology that the magnitude of nocturnal hypoxaemia was an inde-

17

The Alio SmartPatch

pendent predictor of the onset of atrial fibrillation. The new onset of nocturnal desaturations or severe desaturations should prompt treatment to limit the adverse consequences in a CKD patient and, as such, the ability to remotely, non-invasively monitor these parameters is critical in this patient population.

Finally, haemodialysis is dependent on reliable access to the central circulation for repetitive dialysis sessions.

A mature AVF offers the best opportunity for a durable and lasting solution. However, it is still susceptible to a number of potential complications that include stenosis, thrombosis, aneurysms, limb ischaemia, and infection.

Primary patency refers to the time until the first procedure or the occurrence of occlusion—whichever occurs first. Assisted primary patency refers to a vascular access that has been intervened upon prior to failing.

Unfortunately, the literature indicates that up to 50% of AVFs never mature to the extent that they can support haemodialysis, although the ability to intervene early in vascular access dysfunction prior to its failure significantly increases the likelihood of long-term success.

Secondary patency refers to the salvage of a thrombosed arteriovenous access. However, AVFs that have thrombosed have a tendency for early re-thrombosis and, of the usable AVFs, 25% will fail after two years. In general, patency of fistulas and grafts is similar, but grafts tend to require more interventions to maintain adequacy for haemodialysis.

The KDOQI guidelines recommend frequent assessment and monitoring of these access sites every month for signs of malfunction. A well-accepted aspect of the physical examination—as described by Koirala et al in 2016—includes auscultation of the audible characteristics of the access site. These characteristics should generally be of a low frequency, holosystolic, undulating pitch.

Indications of a significant stenosis or impending access failure include an increase in the audible pitch during systole only, harsh amplitudes, or a very weak signal altogether. The absence of a palpable thrill is an additional sign of possible access flow concerns. However, unfortunately, it is often difficult for nephrologists to evaluate the fistula at the time of the patient’s dialysis.

Stenosis leading to thrombosis is the primary cause of AVF failure. This is typically observed at the venous outflow and inflow. Surveillance of fistula or graft patency is an ongoing necessity, and the ability to remotely monitor the audible characteristics of a vascular access would be important in optimising access patency and successful dialysis. In conclusion, patients with CKD and ESKD are complex, and require careful and ongoing monitoring of critical indicators including physiologic parameters, such as heart rate, SpO2, and biomarkers, such as haemoglobin and potassium levels. Those patients with a vascular access in place also benefit from a diligent surveillance system to enhance the long-term patency of their access.

References: References for this article can be found online at renalinterventions. net/alio-smartpatch-wearable-dialysis-patient-monitoring.

DISCLAIMER: Caution - investigational device.

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Issue 3 – May 2022

18

Journal Highlights

Transplantation

Select solid-organ transplant recipients may remain at high Omicron risk despite vaccine boosting While a fourth vaccine dose does increase anti-spike immunoglobin-G (IgG) and neutralising capacity against many COVID19 variants of concern (VOCs), some solidorgan transplant recipients may remain at a high risk for Omicron infection despite receiving vaccine boosters. This is the concluding message of an observational cohort study published in Transplantation.

I

n their report, Andrew Karaba ( Johns Hopkins University School of Medicine, Baltimore, USA) and colleagues state that, because of this, further protective interventions or alternative vaccination strategies should be “urgently explored”. “Additional strategies, such as modulation of immunosuppressant regimens before additional vaccine doses, vaccines with alternative antigen sequences, or broadly neutralising passive immunity products, such as monoclonal antibody cocktails or high-titer convalescent plasma, may be necessary to provide protection in highly immunosuppressed solid -organ transplant recipients,” they write.

The researchers begin by detailing that humoral responses to COVID-19 vaccines Andrew Karaba are attenuated in these patients, necessitating additional booster vaccinations, and that the Omicron variant demonstrates “substantial immune evasion”. It is unknown whether additional vaccine doses increase neutralising capacity of plasma against this VOC among solid-organ transplant recipients, they add.

To evaluate this, the researchers enrolled solid-organ transplant recipients in a national (USA), prospective observational study of immunocompromised COVID-19 vaccine recipients, measuring total anti-S antibody, anti-receptor binding domain (anti-RBD) and angiotensin-converting enzyme 2 (ACE2) neutralisation to VOCs. A total of 25 solid-organ transplant recipients (average age=59 years, 56% female) with low seroresponse were included, and underwent anti-SARS-CoV-2 spike and RBD IgG testing using a commercially available, multiplex enzymelinked immunosorbent assay (ELISA) test both before and after receiving a fourth COVID-19 vaccine dose. Karaba and colleagues detail that surrogate neutralisation was measured against full-length spike proteins of the vaccine strain, and five VOCs, including Delta and Omicron.

Changes in IgG level and percentage ACE2 inhibition (%ACE2i) were compared using the paired Wilcoxon signed-rank test.

Their results are as follows: • A nti-RBD and anti-spike seropositivity increased post-fourth vaccine dose, from 56%

May 2022 – Issue 3

to 84% and 68% to 88%, respectively • Median anti-spike antibody—as measured by World Health Organization binding antibody units—significantly increased post-fourth vaccine dose, from 42.3 to 228.9 • Median %ACE2i also significantly increased against the vaccine strain (5.8% to 20.6%) and the Delta variant (9.1% to 17.1%) • However, neutralisation versus Omicron was poor, did not increase post-fourth vaccine dose (4.1% to 0.5%) and was significantly lower than boosted healthy controls “Although this cohort may not be representative of all vaccinated solid-organ transplant recipients, it does reflect a common and concerning subgroup of persons who seem to be at high risk for SARS-CoV-2 Omicron variant infection despite receiving four vaccine doses,” the researchers write, discussing their findings. “Importantly, at least one participant had evidence of prior infection, which—in combination with three-dose vaccination— connotes potent ‘hybrid immunity’ in the immunocompetent population, yet did not generate Omicron neutralisation.”

The authors acknowledge some limitations of their study, including the fact it was a small, observational convenience sample of people pursuing a fourth COVID-19 vaccine dose in the community and, as such, “may not represent the greater solid-organ transplant recipient population”.

Nevertheless, Karaba and colleagues conclude that these findings suggest that additional and booster dosing of the original vaccines to select solid-organ transplant recipients may not generate robust protection against infection in the form of neutralising antibodies against the Omicron variant, or future variants evolved from Omicron.

“Although this cohort may not be representative of all vaccinated solid-organ transplant recipients, it does reflect a common and concerning subgroup of persons who seem to be at high risk for SARS-CoV-2 Omicron variant infection despite receiving four vaccine doses.”

Retransplantation may offer greater survival outcomes than dialysis following a failed kidney transplant AS PER A CLINICAL STUDY INVOLVING MORE THAN 2,300 adult patients, a second kidney transplant is likely to offer improved survival outcomes when compared to shifting over to dialysis treatment in people whose first kidney graft has stopped functioning effectively. This is the concluding finding of a study in the Clinical Journal of the American Society of Nephrology (CJASN), which compared both options.

For the study, a team led by Rainer Oberbauer (Medical University of Vienna, Vienna, Austria) analysed data pertaining to 2,346 adults with a failed first kidney transplant who were waitlisted for a second kidney transplant in Austria between 1980 and 2019.

At a 10-year follow-up point, patients who received a second kidney transplant had a longer average survival time compared with those who underwent dialysis while remaining on the transplant waitlist, the researchers found. Specifically, patients who underwent retransplantation lived for an average of 5.8 months longer.

The difference in survival time with retransplantation was lower in patients who had a longer wait time after their first transplant failed, however. At the 10-year follow-up point, patients with a waiting time of less than one year who underwent retransplantation had an average of eight months of additional life, while patients who had a waiting time of eight years before undergoing retransplantation gained 0.1 months of additional life, on average.

“Our data showed that a second transplantation is advantageous regarding gained life years; however, the difference to non-transplanted patients decreases with time on the waiting list,” said Oberbauer. “Nevertheless, patients might have a higher quality of life when transplanted and therefore should get a second transplant if a suitable donor organ is available.”

Oberbauer also stressed that patients with a failed first kidney transplant should be waitlisted immediately if they are fit to undergo a second transplantation.

An accompanying editorial in CJASN from Mohammad Kazem Fallahzadeh and Kelly Birdwell (both Vanderbilt University Medical Center, Nashville, USA) notes: “If these results are reproduced in imitated trials from other countries, it would signify the importance of decreasing time on the waiting list for second kidney transplant candidates by measures such as expedited work-up and enlistment of patients with failing first kidney transplants before they require dialysis.”

At the 10-year follow-up point:

8

months

0.1

months

Patients with a waiting time of less than one year who underwent retransplantation had an average of eight months of additional life, on average

Patients who had a waiting time of eight years before undergoing retransplantation gained 0.1 months of additional life, on average

Journal Highlights

19

Transplantation Study findings challenge current immunosuppressant recommendations postkidney transplant failure A PROSPECTIVE, MULTICENTRE COHORT STUDY, PUBLISHED in the Journal of the American Society of Nephrology, has indicated that the prolonged use of immunosuppressants more than one year after kidney transplant failure was not associated with a higher risk of death or hospitalised infection—but was also insufficient in preventing higher anti-human leukocyte antigen (HLA) antibodies or rejection of the failed allograft. In their report, John Gill (University of British Columbia, Vancouver, Canada) and colleagues note that this phenomenon may have been due to inadequate drug exposure. “The findings challenge current recommendations and highlight the need for a controlled trial of immunosuppressant use in patients with transplant failure,” they assert.

Gill and colleagues begin by noting that patients who experience a kidney transplant failure have a high risk of hospitalisation and death due to infection. As such, the optimal use of immunosuppressants after transplant failure “remains uncertain” and clinical practice “varies widely”. Current recommendations suggest discontinuation of immunosuppressants one year after kidney transplant failure, the authors add.

They attempted to elucidate this uncertainty via a prospective cohort study, which enrolled patients within 21 days of dialysis initiation after transplant failure across 16 Canadian centres. Immunosuppressant medication use, death, hospitalised infection, rejection of the failed allograft and anti-HLA panel reactive antibodies were determined at one, three, six, and 12 months, and then twice yearly until either death, repeat transplantation, or loss to follow-up, occurred. Some 269 study patients were followed for a median of 558 days. There were 33 deaths, 143 patients hospitalised for infection, and 21 transplant rejections. The majority of these patients (65%) continued immunosuppressants, while 20% continued prednisone only and 15% discontinued all immunosuppressants.

In multivariable models, patients who continued immunosuppressants had a lower risk of death (hazard ratio [HR], 0.40) and were not at increased risk of hospitalised infection (HR, 1.81) compared with patients who discontinued all immunosuppressants or continued prednisone only. The mean class 1 and class 2 panel reactive antibodies increased from 11% to 27% and from 25% to 47%, respectively, but did not differ by immunosuppressant use. In addition, continuation of immunosuppressants was not protective of rejection of the failed kidney allograft (HR, 0.81).

Transplantation discrepancies contribute to racial disparities in childhood-onset kidney failure survival rates Transplantation discrepancies between Black and white patients have been found to contribute significantly to differing survival rates for childhood-onset kidney failure across the two racial groups.

REPORTING THESE FINDINGS IN the Journal of the American Society of Nephrology ( JASN), Ivonne Schulman, Susan Mendley (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, USA) and colleagues also conclude that equalising time with a functioning transplant for Black patients may help to equalise their survival rates from childhood-onset end-stage kidney disease as compared to white counterparts.

Schulman, Mendley and their co-authors begin by noting that this phenomenon—the role played by kidney transplantation in differential survival for Black and white patients with childhood-onset kidney failure—is currently “unexplored”.

As such, they analysed 30-year cohort data from children beginning renal replacement therapy before the age of 18 years between January 1980 and December 2017 in the United States Renal Data System (USRDS). Schulman, Mendley and colleagues’ analysis identified a total of 28,337 patients within these criteria.

In their JASN report, they detail that Cox regression identified transplant factors associated with survival by race, while the

Mayo Clinic study confirms living kidney donor surgery is low risk for most patients The risk of major complications for people who donate a kidney via laparoscopic surgery is minimal.

That is the conclusion of a 20-year Mayo Clinic (Rochester, USA) study of more than 3,000 living kidney donors, which has been published in Mayo Clinic Proceedings. Only 2.5% of patients in the study experienced major complications, and all recovered completely.

“THE RESULTS OF THIS STUDY ARE extremely reassuring for individuals who are considering being living kidney donors. We found that this lifesaving surgery, when performed at experienced transplant centres, is extremely safe,” said study co-author Timucin Taner (William J von Liebig Center for Transplantation and Clinical Regeneration, Rochester, USA).

The results are “significant”, according to a Mayo Clinic press release, given that nearly 90,000 people in the USA are waiting for a lifesaving kidney transplant. Patients who receive a kidney from a living donor generally have better outcomes, and living donor kidneys also usually function longer than those from deceased donors.

This retrospective, single-centre study is believed to be the largest research study to date to examine the risks associated with living kidney donation via laparo-

survival mediational g-formula was used to estimate the excess mortality among Black patients that could be eliminated if an intervention equalised their time with a transplant to that of white patients.

Black children comprised 24% of the cohort and their crude 30-year survival was 39% compared to 57% for white children (p<0.001), according to Schulman, Mendley and colleagues’ findings.

In addition, Black children had a 45%

Ivonne Schulman

scopic surgery. The study involved 3,002 living kidney donors who underwent laparoscopic living kidney donor surgery at the transplant centre from 1 January 2000 to 31 December 2019. The study tracked complications that occurred up to 120 days after surgery.

Overall, 12.4% of patients had postsurgical complications, predominantly an infection or hernia related to the incision. The researchers found that 76% of those complications happened after the patient was discharged. No patients died, they reported.

“While this study reinforces the safety of this surgical procedure, it does highlight the importance of following up with the donors after donation. That ensures any complications can be treated quickly without any long-term damage,” Taner added.

“While this study reinforces the safety of this surgical procedure, it does highlight the importance of following up with the donors after donation.”

higher risk of death (adjusted hazard ratio [aHR]=1.45; 95% confidence interval [CI]=1.36, 1.54), and a 31% lower incidence of first transplant (aHR=0.69; 95% CI=0.67, 0.72) and a 39% lower incidence of second transplant (aHR=0.61; CI=0.57, 0.65).

The authors detail that children and young adults are likely to require multiple transplants—yet, even after their first transplant, Black patients had 11% fewer total transplants (adjusted incidence rate ratio [aIRR]=0.89; 95% CI=0.86, 0.92). In Black patients, kidney grafts also failed earlier after both first and second transplants, with Black patients spending 24% less of their renal replacement therapy time with a transplant when compared to their white counterparts (aIRR=0.76; 95% CI=0.74, 0.78).

Lastly, Schulman, Mendley and colleagues state that transplantation compared with dialysis strongly protected against death (aHR=0.28; 95% CI=0.16, 0.48), as per time-varying analysis, and mediation analyses estimated that equalising transplant duration could prevent 35% (p<0.001) of excess deaths in Black patients.

Issue 3 – May 2022

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October 2021 Issue 01 www.renalinterventions.net

In this issue:

Twelve-month Wrapsody results at CIRSE 2021 page 4

AN IMPLANTABLE BIOARTIFICIAL kidney device (iBAK) has moved closer to becoming a reality after being awarded a US$650,000 prize from KidneyX. The device’s creator, the Kidney Project, received this award following the first ever demonstration of its functional prototype.

The Kidney Project is a US-wide collaboration led by Shuvo Roy (University of California San Francisco [UCSF], San Francisco, USA) and William Fissell (Vanderbilt University Medical Center, Nashville, USA).

In the past few years, it has successfully tested the two essential components that make up its artificial kidney technology—a haemofilter, which removes waste products and toxins from blood, and a bioreactor, which replic ates other kidney functions, like the balance of electrolytes in blood—in separate experiments.

To secure KidneyX’s Artificial Kidney Prize, the team married these two units in a scaled-down version of the artificial kidney that is roughly the size of a smartphone and evaluated its performance in a preclinical model following successful implantation. The units worked in tandem, powered by blood pressure alone, to provide continuous renal replacement therapy without the need for blood thinning or immunosuppressant drugs. This technology, which is intended to provide patients with improved mobility and physiological outcomes compared to dialysis, will now be upscaled for more rigorous preclinical testing and, eventually, clinical trials.

For the latest step forward in the development of this device, the Kidney Project team was awarded KidneyX’s Phase 1 Artificial Kidney Prize—becoming one of six winning teams selected from a field of innovators across Canada, Israel, Japan, The Netherlands, Portugal, Singapore, South Korea, the UK, and the USA. Other recipient technologies included a wearable, lightweight, dialysate-free artificial kidney (US Kidney Research Corporation) and genetically engineered pig kidneys designed to increase supplies of transplantable organs (Makana Therapeutics).

Profile:

Alexandros Mallios page 12

Dialysis:

Latest debates in dialysis care page 17

Transplantation:

Healthcare disparities in the spotlight page 20

Renal community reckons with removal of race variable in kidney disease diagnosis

Bioartificial device receives KidneyX award after reaching preclinical testing

iBAK device

(Credit: UCSF)

Follow Renal Interventions on all our social media platforms for the latest news, insight and events in kidney care

The National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) have jointly released a report outlining a new race-free approach to diagnosing kidney disease. In its report, the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease recommends the adoption of the new estimated glomerular filtration rate (eGFR) 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation that estimates kidney function without a race variable.

and subsequent treatment of kidney diseases,” said ASN president Susan Quaggin. “By recommending the CKD-EPI creatinine equation refit without the race variable, the task force has taken action and demonstrated how nephrology continues to lead the way in promoting healthcare justice.

It is time for other medical specialties to follow our lead, and NKF and ASN stand ready to help however we can.”

In the USA, more than 37 million adults have kidney diseases and 90% are not aware they have diminished kidney function, the NKF-ASN statement adds, with a disproportionate number of these patients being Black or African American, Hispanic or Latino, American Indian or Alaska Native, Asian American, and Native Hawaiian or other Pacific Islander. These patient groups also face “unacceptable” health disparities and inequities in healthcare delivery.

he task force has also recommended the increased use of the protein cystatin C—a commonly used biomarker of kidney function—combined with serum (blood) creatinine as a confirmatory assessment of GFR or kidney function. The final report, which has been published online in the American Journal of Kidney Diseases (AJKD) and the Journal of the American Society of Nephrology (JASN), was drafted with “considerable input” from hundreds of patients and family members, medical students and other trainees, clinicians, scientists, healthcare professionals, and other stakeholders, to “achieve consensus for an unbiased and most reasonably accurate estimation of GFR”, according to a joint statement from the NKF and the ASN. “This recommendation by the NKF-ASN task force is an important step forward in assuring health and healthcare equity,” said NKF president Paul Palevsky. “We commend the task force for the time, thought, thoroughness and effort it took to explore this issue deeply, and recommend the best path forward for us all. The NKF and ASN urge all laboratories and healthcare systems nationwide to adopt this new approach as rapidly as possible so that we can move towards a consistent method of diagnosing kidney diseases that is independent of race. While the work of the task force is an important initial path forward, both of our organisations are committed to continuing to work to eliminate disparities in the diagnosis and treatment of kidney disease.”

“As the largest organisations representing kidney patients and health professionals, NKF and ASN are committed to eliminating health disparities that harm kidney patients, and ensuring that racial bias does not affect the diagnosis

Developing race-free recommendations Over a 10-month period, the NKF-ASN task force organised its work into three phases. The first involved clarifying the problem and evidence regarding eGFR equations in the USA; the second involved evaluating different approaches to address the use of race in GFR estimation; and the third involved providing recommendations based on this.

In April 2021, the task force published its interim report on reassessing the inclusion of race in diagnosing kidney diseases in AJKD and JASN, asserting that race modifiers should not be included in equations used to estimate kidney function, and that current, race-based equations should be replaced by a substitute that is “accurate, representative, unbiased and provides a standardised approach

T

“The NKF and ASN urge all laboratories and healthcare systems nationwide to adopt this new approach as rapidly as possible so that we can move towards a consistent method of diagnosing kidney diseases that is independent of race.”

Paul Palevsky Continued on page 2

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variables was achieved. The results indicated a statistically significant difference in the time on therapy, which was 18.9 months in the group on remote patient management versus 15.5 months in the group without. There was also no statistically significant difference in the mortality rate.

Clinical News Outset presents home dialysis data at National Kidney Foundation spring clinical meetings

Outset Medical has announced the release of three new datasets related to home dialysis—each of which were presented during the National Kidney Foundation (NKF) spring clinical meetings (6–10 April 2022; Boston, USA). The results from scientific papers shared by the company highlight patient and nephrologist views on home haemodialysis (HHD) adoption and the hidden costs of peritoneal dialysis (PD).

The first of these involved a national survey of 202 dialysis patients, which found that 72% viewed the features of Outset’s Tablo haemodialysis system as a “significant clinical improvement” in HHD. In addition, 77% said the Tablo’s features would make them more likely to try home haemodialysis.

A second national survey of 184 nephrologists found that 77% said the features of Tablo were a significant improvement over existing HHD devices, while 98% said these features would make them more likely to recommend HHD to their patients.

A third dataset evaluated the cost of PD failure—which is associated with a near-100% risk of hospitalisation during the six months preceding discontinuation. The study found that more than US$72,000 is spent per patient in the three months before and three months after PD failure. Further, after the transition from PD to in-centre haemodialysis, hospitalisations remain higher for former PD patients over time.

Ajay Kirtane

ReCor announces results of pooled data analysis from two renal denervation studies

ReCor Medical and Otsuka Medical Devices have announced that Ajay Kirtane (Columbia University Irving Medical Center, New York, USA) recently presented a pooled data analysis from ReCor’s two randomised trials evaluating the Paradise ultrasound renal denervation (uRDN) system for the treatment of hypertension at EuroPCR 2022 (17–20 May, Paris, France).

The analysis demonstrated a statistically significant reduction in blood pressure across a broad range of hypertension severity, as represented in the RADIANCE-HTN SOLO and TRIO studies. It was presented in a latebreaking session on World Hypertension Day, and combined data from 282 patients randomised in these two

prospectively powered, sham-controlled studies enrolling two disparate patient populations: patients with resistant hypertension (TRIO) and patients with mild-to-moderate hypertension (SOLO).

There were consistent benefits in both blood pressure reduction and medication burden across the pooled patient population compared to sham.

The combined dataset showed an overall between-group difference through six months that favoured uRDN in daytime ambulatory systolic blood pressure (-4.8mmHg) and home systolic blood pressure (-5.4mmHg).

“The results of this pooled analysis make clear the consistent blood pressure-lowering effect that uRDN can have across differing severities of hypertension, regardless of trial design and whether the enrolled patients are on or off antihypertensive medications,” said principal investigator Kirtane. “Assuming continued safety of the procedure is demonstrated, uRDN is a promising treatment option complementary to lifestyle modification and medications for patients with uncontrolled hypertension.”

Cibiltech begins enrolment for clinical trial monitoring kidney transplant patients with artificial intelligence

Cibiltech has announced that the first patient has been enrolled in the CIBIL study—a prospective randomised controlled trial to assess the use of an artificial intelligence (AI)-based software predicting allograft survival in the followup of kidney transplant patients.

Cibiltech claims this marks the beginning of a “first-of-its-kind” clinical trial conducted in Europe evaluating a digital health solution. It will involve Predigraft, which is a CE-marked, class 2a medical device intended to offer physicians and hospitals an easy-touse platform that simplifies access to data and decision-making. Predigraft embeds the iBox algorithm, a unique AI technology predicting individual, longterm kidney allograft survival.

“Following promising preliminary results, we are now looking forward to seeing the clinical benefits of using the iBox as an early intervention monitoring tool for kidney transplant patients,” said Alexandre Loupy (Paris Transplant Group, Paris, France).

Restorative Axess graft demonstrates promising patency and safety in firstin-human study

The preliminary results from a first-inhuman clinical trial assessing Xeltis’ restorative haemodialysis access graft, Axess, have shown promising early puncturing, patency and safety data.

These findings were presented for the first time by trial investigator Matteo Tozzi (University of Insubria, Varese, Italy) at the Charing Cross Symposium (CX 2022; 26–28 April, London, UK).

Axess is a synthetic, biocompatible blood vessel, which, over time, is colonised by the patient’s own tissue following implantation and becomes a living vessel via the process of

21

Axess graft

endogenous tissue restoration. To date, it has been implanted in 11 end-stage kidney disease patients, with a median follow-up time of 6.5 months, across five European sites as part of the Axess study. Overall, more than 600 dialysis sessions have been enabled in this patient group, with puncturing—or dialysis initiation—starting as early as two weeks after implantation in some patients.

Preliminary data analysis shows “very promising outcomes” on primary endpoints, in addition to 100% rates of functional patency and safety, with no aneurysms or infections reported, and “excellent ease-of-use” for surgeons and dialysis nurses. “Our first clinical experience using the Axess device is extremely encouraging,” said Tozzi.

“This fully synthetic graft is easy to implant, can be promptly punctured and exhibits an excellent safety profile.

Its potential to turn into a longer-lasting natural vessel is an additional benefit and suggests that an optimal solution for dialysis patients may be within our reach.”

Baxter presents data indicating Sharesource increases time on home dialysis by several months

Baxter International has announced new data indicating the use of its Sharesource remote patient management platform with an automated peritoneal dialysis (PD) cycler may improve the clinical effectiveness of dialysis care for kidney patients by extending their time on home therapies by 3.4 months.

These data were presented during the World Congress of Nephrology (WCN’22; 24–27 February, Kuala Lumpur, Malaysia) and pertain to a retrospective study that included nearly 1,500 home PD patients receiving care at Baxter Renal Care Services clinics in Colombia. The study took place between 2017 and 2019, with a twoyear follow-up in 2021.

Sharesource, which is designed to allow healthcare professionals to monitor their patients’ home dialysis treatments, and then remotely adjust therapy without the need for patients to make unplanned visits to the clinic, has also been shown to reduce hospitalisations and costs, travel to clinical facilities and wait times.

The study presented at WCN’22 was a retrospective cohort analysis of incident patients—defined as those who reached and continued automated PD from day 90—that compared outcomes for those receiving automated PD with or without remote patient management.

The methodology included time until death, with censorship for technique failure, kidney transplantation, treatment suspension, abandoned therapy or transfer to a different clinic.

Using propensity score matching, an adequate balance in the predictive

Humacyte announces publication of positive long-term data from bioengineered graft study

Humacyte has announced that fiveyear data from a phase 2 clinical trial of haemodialysis patients receiving its bioengineered graft, the investigational Human Acellular Vessel (HAV), for arteriovenous access have been published in the European Journal of Vascular and Endovascular Surgery (EJVES) companion journal EJVES Vascular Forum.

The manuscript reports the durable long-term use and ongoing clinical function of the HAV in end-stage kidney disease patients undergoing haemodialysis. These phase 2 followup data demonstrate that the HAV was observed to provide routine and functional haemodialysis access for patients who require dialysis three times a week. At month 60, patency allowing for reliable dialysis access cannulation was estimated at 58.2% of evaluable patients (after censoring for deaths and withdrawals). While there was no comparator in its trial, Humacyte claims this rate compares favourably to historical reports of five-year functional patency rates in arteriovenous fistulas.

In addition, no infections were reported during the five-year followup period, with the HAV being welltolerated and non-immunogenic.

QSant test

NephroSant launches two-year AQUA study involving 2,000 kidney transplant recipients

NephroSant has announced enrolment of the first patient in the AQUA study, assessing the use of its non-invasive, urine-based QSant test for the early detection of kidney allograft rejection risk. Eligible participants will have undergone kidney transplantation within 90 days of enrolment, with up to 2,000 individuals being enrolled and followed for 24 months, during which time they will be assessed for signs of acute rejection through QSant testing as well as standard-of-care diagnostics.

During the 24-month study period, the number of biopsies, rejection events and hospitalisations as well as changes in medication for each participant will be recorded. Following the conclusion of the study, these metrics will be compared to those of a retrospective, site-matched cohort of kidney transplant recipients to demonstrate QSant’s performance in comparison to the standard of care for detecting and facilitating early intervention of acute transplant rejection events.

Issue 3 – May 2022

22

Latest News

Industry News Nipro to bring Cronus high-pressure PTA balloon catheter to USA

Nipro Medical Corporation is set to introduce its second-generation Cronus high-pressure (HP) percutaneous transluminal angioplasty (PTA) balloon catheter to the US market.

Cronus HP is indicated for use in popliteal, femoral, iliac, and renal arteries, and in the treatment of arteriovenous fistulas (AVFs). It is intended for use by vascular surgeons and interventional nephrologists alike attempting to repair and restore AVFs in haemodialysis patients.

Foundational characteristics of Cronus HP include strength, flexibility and durability at high pressures, the ability to aid in using only one balloon during a procedure, facilitating entry across the lesion, and helping to minimise ‘balloon dog-boning’ and address difficult stenoses.

Nipro’s vascular division, newly established in April 2021, already features nine products across three categories, including intravascular imaging.

DaVita Kidney Care appoints new chief medical officer of home modalities

DaVita Kidney Care has announced the appointment of Mihran Naljayan (Louisiana State University School of Medicine, New Orleans, USA), who is board-certified in nephrology and hypertension through the American Board of Internal Medicine, as its new chief medical officer of home modalities.

Naljayan joined DaVita in 2016 and most recently served as vice president of clinical affairs within the company’s home dialysis programme. In that role, he created and led DaVita’s home physician support network—a programme intended to help empower nephrologists to advocate for home dialysis with eligible patients. Since Naljayan joined, DaVita has seen a 35% increase in home haemodialysis and peritoneal dialysis treatments.

He succeeds Martin Schreiber, who has led DaVita’s home dialysis programme since 2014. Schreiber will continue to serve DaVita’s home patients in a part-time capacity as a consultant for several strategic initiatives, including 11 newly launched, value-based care programmes that aim to increase access to home dialysis.

Versi PD cycler system

Fresenius’ Versi peritoneal dialysis cycler system gains FDA clearance The US Food and Drug Administration (FDA) has awarded 510(k) clearance to Fresenius Medical Care North America (FMCNA) for its Versi peritoneal dialysis May 2022 – Issue 3

(PD) cycler system—a next-generation automated peritoneal dialysis (APD) system. Fresenius claims that Versi PD is “the lightest, smallest and quietest dialysis cycler in the USA”. The simple, portable device is designed to improve health equity by making home therapy a more feasible option for a broader population of dialysis patients.

Intended to enhance the patient experience, Versi PD allows patients to enjoy restful sleep through its almost silent operation, fewer disruptive alarms, and night mode. The cycler also has the capability of more personalised prescription programming to meet the individual needs of a broad range of patients. It offers a large, intuitively designed touchscreen, as well as embedded videos with audio guidance to assist patients step-by-step through setup and treatment. The cycler battery and custom cart facilitate mobility around the home, which can further improve a patient’s quality of life.

Versi PD will begin a limited rollout in 2022, with more widespread availability planned in 2023 and beyond.

Bio-Techne announces Thermo Fisher Scientific agreement for kidney transplant rejection assay

Bio-Techne has announced an agreement with Thermo Fisher Scientific to exclusively complete development of and commercialise the ExoTRU kidney transplant rejection test, which was developed by Exosome Diagnostics—a Bio-Techne brand.

ExoTRU is a non-invasive, multigene, urine-based liquid biopsy assay designed to provide critical allograft health information to assist clinician decision-making in managing kidney transplant patients and optimising patient care. To this end, the assay has the potential to discriminate between T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR).

ExoTRU was developed in collaboration with the Azzi Laboratory at the Transplantation Research Center of Brigham and Women’s Hospital, Harvard Medical School (Boston, USA).

Medtronic issues voluntary recall for subset of IN.PACT DCBs due to pouch damage Medtronic has voluntarily recalled a subset of its IN.PACT Admiral and IN.PACT AV paclitaxel-coated percutaneous transluminal angioplasty (PTA) balloon catheters due to the potential for pouch damage resulting in a loss of sterility. This is according to a news alert from the company dated 31 March 2022.

Medtronic communicates that approximately 6,000 IN.PACT Admiral catheters and three IN.PACT AV catheters distributed to customers globally are impacted by this recall.

“Medtronic is communicating to customers with affected products on hand to immediately quarantine and return the product to Medtronic, as well as send back a signed confirmation form,” the company details.

The news alert continues: “The pouch

IN.PACT AV DCB

damage was discovered during a routine inspection. Upon investigation, a change implemented to one manufacturing line was determined to be the cause. All batches manufactured on this line after that change are being retrieved. The problem on that line was fixed. Additionally, to ensure that no further issues, production on all lines was paused until a follow-up packaging inspection was completed. No further errors were discovered.”

The company claims to have received zero complaints involving this issue with two of its drug-coated balloon (DCB) products. In addition, it reports that there have been zero reports of injury or death related to it. “There are no actions required for patients where the affected IN.PACT Admiral and IN.PACT AV catheters were used during a procedure. Patients should continue to be monitored in accordance with the medical facility’s standard care protocols,” the news alert reads.

Medtronic stresses that, for most regions, there is little or no impact for customers to order a replacement product, also noting that no other Medtronic products are affected by this issue and that all appropriate regulatory bodies have been notified.

Diality secures US$24 million funding round to support development of haemodialysis system

Diality has announced the close of a US$24 million Series B2 investment round. This funding will be used to support US Food and Drug Administration (FDA) 510(k) clearance of the company’s versatile haemodialysis system—including preparing for a home clinical study and building a US commercial organisation.

Diality is looking to fill what it describes as a “lingering market gap” with a best-in-class haemodialysis system that is capable of delivering the intense dialysis doses commonly prescribed to patients receiving three dialysis treatments per week, but also lower-intensity doses suitable for more frequent dialysis.

The company intends to meet the needs of prescribing physicians and their patients in acute, sub-acute, chronic and home settings by providing a cost-effective, and user-friendly, solution. The performance characteristics of this product have not been established, however, and it is not yet available for use in the EU or USA, pending CE-mark approval and submission to the FDA for clearance.

Alio remote monitoring technology receives first FDA 510(k) clearance Alio has announced receipt of US Food and Drug Administration (FDA) 510(k) clearance for its remote monitoring

system, which is intended for use by healthcare professionals to intermittently collect physiological data—including skin temperature, auscultation sound data and heart rate—in home settings.

The company’s technology, the Alio SmartPatch device, provides real-time, 24/7, non-invasive remote patient monitoring and, by sharing clinical data, intends to make it possible for caregivers and clinicians to enable better care. It has the potential to serve as a remote patient monitoring system for a number of conditions.

“Remote patient monitoring is by no means a new concept in the patient care landscape, but advancements in the technology that is deployed have lagged behind,” said Richard Neville (Inova Health System, Falls Church, USA).

“Patients should be able to benefit from the latest innovations technology has to offer. The Alio clearance is a step in the right direction in terms of ushering in a new era of remote patient monitoring.”

This is the first of several intended regulatory submissions for the company. Alio is currently undergoing clinical investigations to assess additional indications for use in remote patient monitoring of electrolytes, fluid management, and fistula status, as well as specific patient populations, such as chronic care patients with conditions like end-stage kidney disease (ESKD), patients undergoing haemodialysis, and patients with heart failure and peripheral vascular disease. At present, however, Alio’s primary focus is the management of ESKD.

Vascular Therapies closes US$25 million to advance proprietary sirolimus formulation

Vascular Therapies has announced the closing of US$25 million in private financing. The financing in question comprised of both existing and new investors, including a Fortune 100 global healthcare company.

The company plans to use the proceeds to further advance Sirogen— a proprietary sirolimus formulation for intraoperative, local, perivascular drug delivery—via clinical research, including with its ACCESS 2 study.

In Vascular Therapies’ first phase 3 clinical study, dubbed ACCESS, the primary endpoint was not achieved.

However, a post hoc subgroup analysis revealed significantly improved arteriovenous fistula maturation with therapeutic durability in end-stage kidney disease patients aged 65 years and older.

In light of this recent funding breakthrough, Vascular Therapies is now focused on initiating enrolment of the 120-patient ACCESS 2 randomised clinical study, which aims to validate the encouraging post hoc results seen with Sirogen in high-risk patients and is expected to start in the second quarter Richard Neville of 2022.

23

Events

4–8 June

American Transplant Congress (ATC) Boston, USA www.atcmeeting.org

6–9 June

Leipzig Interventional Course (LINC) Leipzig, Germany www.leipzig-interventional-course.com/ visitors/linc-2022 Please be advised that the events listed opposite, because of COVID-19, are subject to change. Please check the relevant website for further details as the event may be cancelled, postponed, or become a virtual event.

7–9 June

UK Kidney Week (UKKW) Birmingham, UK www.ukkw.org

9–11 June

Vascular Access for Hemodialysis Symposium Charleston, USA www.vasamd.org/events/2022-symposium

11–16 June

Society of Interventional Radiology (SIR) Annual Scientific Meeting Boston, USA www.sirmeeting.org

15–18 June

Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM22) Boston, USA www.vascular.org/vam-2022

24–25 June

Endo Vascular Access (EVA) Meeting Patras, Greece www.evameeting.org

11–14 August

International Society for Peritoneal Dialysis (ISPD) Congress Singapore www.ispd2022.com

5–7 September

British Transplantation Society (BTS) Annual Congress Belfast, UK www.bts.org.uk/events-meetings/bts-annualcongress-2022

Meet our editorial board Nicholas Inston

Ziv Haskal

Stephen Hohmann

Robert Jones

Chairman of Executive and Editorial Board

Board Member

Board Member

Board Member

Nicholas Inston is a transplant and vascular access surgeon, and the clinical service lead for renal surgery, at Queen Elizabeth Hospital in Birmingham, UK.

Ziv Haskal is a professor of radiology, and an interventional radiologist and interventional oncologist, at the University of Virginia School of Medicine in Charlottesville, USA.

Stephen Hohmann is a vascular and general surgeon at the Texas Vascular Associates clinic in Dallas, USA.

Robert Jones is an interventional radiologist at Queen Elizabeth Hospital in Birmingham, UK.

Issue 3 – May 2022