NephMadness 2015: Nephrology and Vascular Surgery Region

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Every year the surgeons crash the party and find a way to get a region all to themselves. Last year the urologists sat atop the Kidney Stone region and this year it is the vascular surgeons turn. The region has a diverse group of teams from various conferences. The PD Conference sent its two top teams, open and laparoscopic PD catheter placement (Acute PD, last year’s cinderella was derailed by the PD Fluid shortage and was relegated to the NIT). Arteriovenous access monitoring was riding high after its win in the KDIGO tournament and set up the classic rivalry of traditional monitoring of graft health versus specific tests to look for early trouble. The catheter lock controversy shows that details matter, and lastly the matchup of vascular biology concepts shows that research is moving forward in all aspects of dialysis.

Selection Committee member for the Vascular Surgery Region:

Lee, TimmyTimmy Lee, MD, MSPH

Dr. Lee received his medical degree from the Louisiana State University Health Sciences Center in Shreveport and his residency and nephrology fellowship the University of Alabama at Birmingham. Dr. Lee’s research focuses on two main areas in hemodialysis vascular access. The first focuses on understanding the pathophysiology and mechanisms of dialysis access stenosis using clinical and experimental models. The second research area focuses on research to improve the processes of care to improve hemodialysis access placement and outcomes. Currently, Dr. Lee is an Associate Professor of Medicine, Director of Associate Director of Interventional Nephrology, and Associate Director of the Nephrology Fellowship Program at the University of Alabama at Birmingham, and Director of Dialysis at the Birmingham Veterans Affairs Medical Center.

Meet the Competitors for the Nephrology and Vascular Surgery Region

Surveillance of AVG
Clinical Monitoring of AVG

Laparoscopic PD Placement
Open PD Placement

Upstream Hemodynamics
Downstream Vascular Biology

Prophylactic Abx Cath Lock
Heparin Catheter Lock

Surveillance of AVG vs Clinical Monitoring of AVG

This is the ultimate matchup of high tech versus low tech, offence versus defense. Can surveillance of a patient’s access with ultrasound provide long-term access patency over simple clinical monitoring? This could be a true game changer. The median time from graft creation to permanent failure is ~2 years. The vast majority of these failures are from irreversible thrombosis. Stenosis is a major risk factor for thrombosis. Our goal is to perform either surveillance (high tech) or clinical monitoring (low tech) of AVGs with an aim to identify those with a greater than 50% stenosis. Once discovered, the patient is sent to angiography for potential intervention with the hopes of preventing AVG thrombosis. Let’s take a look at both of these in greater detail.

Surveillance of AVG

Surveillance is the ultimate in defense. We’re talking the Tony Bennett, University of Virginia style defense. Monthly screening is required with the hope of finding a stenosis and intervening before eventual thrombosis develops. The ultimate test for identifying a stenosis is angiography. However, this is invasive and expensive. Therefore, non-invasive strategies such as ultrasound and Transonic technology in the dialysis unit have been employed to help screen for potential stenosis. The basic premise is that when a stenosis is present you will notice an increase in intragraft pressure and a decrease in access blood flow.

3 main forms of graft surveillance:

  1. Static dialysis venous pressure: This is measured by hooking up a manometer to the arterial dialysis needle prior to beginning dialysis. The intragraft pressure is then normalized to the systemic blood pressure. This is termed static venous pressure ratio (SVPR). As stenosis worsens this value would be expected to increase.
  2. Intra access flow monitoring: This technique uses the Fick principle. After reversing the arterial and venous lines, ice-cold saline is quickly injected via the arterial port. The greater the access blood flow, the quicker the rise in blood temp following injection. A computer algorithm can then compute the area under the curve and thus the flow. This was the preferred monthly method for surveillance by KDOQI 2006 guidelines.
  3. Duplex ultrasound: This method is typically performed by radiology and is most costly. It involves measuring peak systolic velocity at anastomoses and sites with visual stenosis. The ratio of peak systolic velocity at the stenotic site and the peak systolic velocity immediate upstream of greater than 2 has a 80% positive predictive rate for angiographically demonstrated stenosis.

These surveillance forms are all great at finding stenosis. However, that is not the real question at hand. Do they predict graft thrombosis? Allon et al looked at 4 studies that showed the positive predictive value ranging between 0.25 and 0.43 and even worse a false-positive rate ranging between 0.08 and 0.24. All being told, many will have a positive test and never go on to thrombose and others will have a negative test that will eventually thrombose. Paulson et al went on to show in a meta-analysis that flow monitoring was unable to identify the subset of patients with stenosis that went on to thrombose.

Clinical Monitoring of AVG

Clinical monitoring refers to physical examination or review of laboratory studies. This is standard of care and actually is not that bad. What does this include.

  • Inspection, physical exam (absence of thrill, distal edema)
  • Auscultation
  • Difficult cannulation, aspiration of clots
  • Prolonged bleeding after cannulation
  • Decrease in Kt/V

A combination of these clinical parameters has a 69-93% positive predictive value for angiographically confirmed stenosis. Clinical monitoring is free. This is compared to an expensive ultrasound machine that needs constant maintenance. Moreover, additional staff and training are required for running a surveillance program. However, the success of this approach is directly related to the proficiency and consistency of the dialysis staff performing the monitoring. Furthermore, clinical trial results using clinical monitoring vary considerably across trials and may be difficult to translate to the real world where variations will only increase further.

Let’s take a look at the head to head match-up

A 2015 meta-analysis reported in Seminars in Dialysis examined 7 randomized controlled trials. These were all relatively small studies ranging from ~50 to 140 patients. The data are pretty slim and really don’t show a benefit. Furthermore, they show more invasive studies that don’t lead to hard outcomes. This meta-analysis concluded that AV access surveillance using access blood flow monitoring to lower the risk of thrombosis is of uncertain benefit and varies substantially between AVG and AVF. As such, no consensus was possible concerning the utility of access blood flow monitoring to predict stenosis and ultimately thrombosis in vascular access. Vascular access issues account for a huge (estimated at ~50%) amount of the total dialysis cost and are directly related to morbidity, so it is important that a proper clinical trial be performed. However, we are still routinely performing surveillance without much clinical evidence. Which team will take NephMadness — the defensively minded surveillance or the offensively minded clinical monitoring?

Laparoscopic PD Placement vs Open PD Placement

A real game changer in the field of surgery was the dramatic uptake in the use and refinement of laparoscopy. The use of laparoscopy leads to reductions in pain, bleeding, and sometimes even morbidity compared with open surgery. There is also improvement in recovery time and infection. However, the use of laparoscopy for the placement of PD catheters has lagged behind. Why is this? Well, the key to successful long-term PD (a lifeline for patients) is the presence of a well-functioning dialysis catheter. Open surgical placement offers the potential for optimal use. As such, the open technique is still the most commonly performed. However, the use of the laparoscopic technique for PD catheter insertion is seeing a huge upsurge.

Laparoscopic PD Placement

The first successful description of PD was in 1959 by Richard Ruben. Since this time refinements have been made to improve the longevity of this modality. Just as the AV access is the achilles heel in hemodialysis, the PD catheter is the achilles heel in PD. As such, placement of the Tenckhoff catheter is an important consideration in how long and well the catheter functions. The use of the laparoscope to place the PD catheter represented a potential way to improve the long term function of the catheter with direct visualization. The technique involves insuflating the abdomen with air with direct visualization while placing the Tenckhoff catheter in the abdomen. Other advantages are the ability to perform simultaneous surgeries such as lysis of adhesions or even hernia repair or appendectomy.

Open PD Placement

The most commonly used method for placement of a PD catheter is the open technique. This technique has been around the longest as well. This technique is the quickest and relatively cheap. While general anesthesia is needed, there is no need for a fancy laparascope. While the procedure itself might be quick, the recovery is longer than with the laparoscopic technique. Lastly, the learning curve is less steep with the open approach with no need to learn to drive and operate a laparoscope and trocar system.

Let’s compare and contrast

The laparoscopic technique takes significantly longer to perform than open surgery (~14 vs ~22 minutes). However, a study of 50 patients randomized between open versus laparoscopic PD catheter insertion showed no difference in the early complication rate.

A recent meta-analysis published in PLOS one compared the two techniques. This study included 3 randomized controlled trials and 8 cohort studies. They found:

  • No difference
    • – In the risk of developing an exit-site/tunnel infection.
    • – In PD fluid leakage
    • – In revision of poorly functional catheter
  • Laparoscopic approach had
    • – better 1-year survival of catheter
    • – less catheter migration
    • – numerically but not a statistically significant less obstruction
    • – borderline improved 2-year survival of catheter
  • NNT of 8 for preventing one migration using laparoscopy over open approach
  • NNT of 6 for one more catheter reaching 1-year using laparoscopy over open approach

This meta-analysis concluded that laparoscopic approach is superior to the open approach. They also suggest that the laparoscopic approach would result in more postoperative comfort and less cost. However, not all of the studies included in this meta-analysis measured all of the outcomes so it is difficult to make definitive conclusions. Furthermore, these were small studies that typically only spanned 1 or 2 centers. A definitive trial will likely never be performed. Typically the choice between open and laparoscopic is made by surgeon experience and preference. It will be a tough match, but it appears like the laparoscope has the advantage.

Upstream Hemodynamics vs Downstream Vascular Biology

The biological process governing the formation of working access is complex. The process involves the arterialization of a vein in a coordinated manner that allows for patent entry and exit of blood flowing at a high rate. However, it is not so easy. A large randomized clinical trial performed in the US with 877 patients showed that ~60% of AVFs fail to mature enough to even begin dialysis is the first place. This is astounding. It is no surprise that there are concerted effort to understand the reasons for this abysmal result. This is a story of the reductionists and the engineers. Who will take NephMadness gold?

Upstream Hemodynamics

Team Upstream Hemodynamics have been around the block for a while but only recently has it experienced a huge upsurge in popularity. The principle of upstream is quite simple and takes its lead from other forms of vascular injury like atherosclerosis and coronary artery disease. The fundamental concepts to know are the difference between laminar flow and disturbed flow. To distill this down to the basics you have to understand that endothelial cells love smooth laminar flow wall shear stress.

  • Laminar flow: endothelial cells “turn on” an atheroprotective, antithrombotic, antioxidant phenotype.
  • Disturbed flow: low and reciprocating wall shear stress leading to an atherogenic, thrombogenic, proinflammatory phenotype.

In atherosclerosis lesions occur at sites where flow is not laminar such as the carotid and coronary bifurcations and the branching points of the renal and femoral arteries. This is the same for arteriovenous fistula (AVF). Neointimal overgrowth (hyperplasia) in the AVF typically occurs at areas where disturbed flow is present.

What factors influence hemodynamics

  1. The surgically created anastomosis- creates complex conditions
  2. The nonuniform actual anastomosis- leads to areas of disturbed flow
  3. Antegrade or retrograde flow in distal artery in end-to-side anastomosis
  4. Configuration of the anastomosis

How can knowledge of these factors improve vascular access? First, you can improve the vascular surgery of AVF creation to minimize these untoward hemodynamic events. More 3D real-time imaging of AVF to document areas of disturbed flow to then improve surgical technique in future AVF creations. More careful planning of the surgical technique to ensure proper anatomy for a best-case scenario.

Downstream Vascular Biology

The creation of arteriovenous access represents a critical transition point in a patient’s life with kidney disease. However, the biology of access formation during the intense inflammation observed during CKD and uremia could disrupt successful access maturation. What is known about this process?

First, we need to look at the histopathology of vascular access dysfunction. If you look at a non matured AVF under the microscope you see a picture of an overly aggressive venous neointimal hyperplasia. This appears to be an overgrowth of myofibroblasts, fibroblasts, and contractile smooth muscle cells within the typically delicate intimal layer of the vessel. This leads to a scenario in which the vein tilts towards a more contractile phenotype. The stenotic arteriovenous graft appears much the same with aggressive neointimal overgrowth, more matrix deposition and neovascularization of the adventitia.

What about the repair process that occurs after balloon angioplasty? This is the primary intervention used to treat stenosis. Well, often times this actually accelerated the neointimal overgrowth that led to the stenosis in the first place. This is especially true in the patient with uremia and chronic inflammation.

Deleterious issues related to the substrate in which the fistula or graft is created likely plays a role as well. A report suggested that ~90% of veins sampled at the time of access formation in patients with CKD already had neointimal overgrowth. This may be a set-up for failure from the very beginning. Many also have pathologic calcification of the vessel as well.

What are some of the pathways affecting access maturation?

  • Heme oxygenase 1 (HO-1): This enzyme, which catalyzes the degradation of heme, is upregulated during vascular injury. This upregulation induces protection from inflammation, oxidant stress, and vascular proliferation. Studies in patients with AVFs show that excessive length polymorphisms (GT repeats) in the HO-1 promoter (leading to less HO-1) are more common in patients with AVF maturation failure. These findings were also seen in a mouse model of AVF (more AVF failure in HO-1 knockout mice).
  • Oxidative stress: The use of tempol (a superoxide anion scavenger) in another mouse model of AVF showed improved blood flow and less neointimal overgrowth.
  • Monocyte chemoattractant protein 1 (MCP-1): This is a potent chemokine (for monocytes and macrophages) that has been identified to play a key role in atherosclerosis. Juncos et al demonstrated that MCP-1 knockout mice had increased AVF patency at 6 weeks after creation.
  • Endothelial dysfunction: A clinical study assessed endothelial function in patients with CKD about to undergo AVF creation. This group used the brachial artery flow-mediated vasodilation (FMD) approach and demonstrated that enhanced FMD lead to enhanced remodeling and diameter of the AVF. Likewise a rat model in which L-NAME was used to inhibit nitric oxide (and thus endothelial function) led to significantly more neointimal overgrowth.

The problem with the downstream vascular biology team is that they are still in the development stage (think McDonald’s All Americans). Full of promise but nothing to really hold their hat on. What is in the pipeline? Endothelial cell-loaded gel foam wraps, recombinant elastase therapy, drug-eluting stents, drug-coated balloons, far-infrared therapy, and even completely synthetic tissue cultured grafts are all in the offing. Overall, the prospects look great but we need to see some results on the court. Downstream Vascular Biology could be a Cinderella in this year’s NephMadness.

Prophylactic Antibiotics Catheter Lock vs Heparin Catheter Lock

Defense reigns supreme in this matchup. Tough zone prevention defense guarantees you won’t see a high-scoring game. Team Antibiotics has proven success but remains controversial in their ability to be seen more than a mid-major. They are akin to Gonzaga (the perennial Cinderella pick)–everyone pulls for Gonzaga in the NCAA tournament but during the year they are all but forgotten. Team Heparin is everyone’s favorite lock-down defensive powerhouse, like Arizona this year. Too bad they are on the West coast or maybe the rest of us could actually watch them play.

There is a concerted effort to have as many patients as possible using either a fistula or graft for hemodialysis access. However, this is not always possible. Thus, a considerable number of patients are dependent on catheters for access. Therefore, it is imperative that these catheters stay both clot and infection free. A potential answer to this problem is to fill (or lock) the catheter with either antibiotics or heparin to prevent these untoward events.

Prophylactic Antibiotics Catheter Lock

The rate of catheter related bloodstream infection is reported anywhere between 2.5 to 6.6 per 1000 catheter days reported. The rate of infection has remained quite steady of the last decade and is estimated to be ~40,000 per year. These lead to considerable morbidity and mortality. There have been several randomized trials showing that antimicrobial locks of dialysis catheters reduced blood stream infections. A meta-analysis published in the Annals of Internal Medicine concluded that the use of antibiotic locks resulted in less bacteremia and catheter removal. But, there was quite a bit variability in the studies included in this meta-analysis. However, the practice has not been widely utilized. In fact, the CDC and the Infectious Disease Society of America have not recommended the routine use for fear of developing antimicrobial resistance. A recent prospective, multicenter, observational cohort study by Moore et al was published in CJASN. This study compared gentamicin/citrate lock versus heparin in patients on hemodialysis with a catheter. The results were actually quite striking:

  • ~73% reduction in catheter-related bloodstream infections
  • Reduction in mortality! this is impressive
  • No increase in gentamicin-resistant organisms

Another study looking at cotrimoxazole + heparin versus heparin alone dialysis catheter lock found similar results.

  • Less infection with cotrimoxazole
  • However, no change in catheter removal or thrombosis

What happens if prophylactic antibiotic catheter locks becomes widespread in their use? Also, these trials only covered 6 months to a few years. What happens to bacterial resistance after 5 or even 10 years? This could lead to widespread resistance. However, it is hard not to see the benefits for patients as they would have much less infection and potentially even a mortality benefit. However, if widespread resistance occurs then this could lead to even worse infections that are now drug resistant. This will be a tricky issue and will need to help from our ID experts.

Heparin Catheter Lock

Locking catheters with heparin is a common strategy to prevent clotting. However, the practice has risks associated as well. First, is the concern of heparinizing the patient systemically and causing bleeding. The other major concern is the development of heparin-induced thrombocytopenia (HIT). This is a feared complication as it portents a dismal prognosis. Heparin has its competition. There is team citrate and team tPA. These have both been gaining steam. A recent systematic review and meta-analysis published in AJKD compared the use of heparin and citrate. 13 randomized trials (~1700 patients) met the inclusion criteria for this review. However, only 3 trials compared heparin to citrate alone. The other trials had a combination of citrate with various antibiotics.

Below is a summary of the 3 citrate versus heparin trials.

  • No difference in infections
  • More bleeding with heparin versus citrate locks
  • No difference in exit-site infection
  • No difference in catheter removal for poor flow
  • No difference in thrombolytic treatment

Those who are hematologic fans will chose heparin and those who are ID fans will chose antibiotics. Which one would you rather have–a clotted access or an infected access? Tough choice!

– Post written and edited by Drs. Matthew Sparks and Timmy Lee.

Neph_Madness

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