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This bracket offers teams from the past, present and hopefully the future of the management of acute and chronic renal failure. The glaring omission of transplantation from this section has resulted in a potential planned boycott of this bracket by transplant nephrologists, recipients and donors. However, as 90% of patients receive dialysis prior to transplantation and over 90% of nephrologists are not transplant physicians, the steering committee has respectfully declined to change the seeds citing the dominant win of Transplant in last year’s inaugural NephMadness. Like Kentucky, champion one year and NIT the next. It’s going to be a spirited and competitive contest of physiologic principles and access techniques matched against research proposals. Who will achieve maximum clearance and filter their way to the championship?

Selection committee member for the Renal Replacement Therapy Bracket:

Glenn Chertow, MD, MPH
Normal S. Coplon/Satellite Healthcare Professor of Medicine
Chief, Division of Nephrology
Stanford University School of Medicine

Dr. Chertow is a renowned clinical researcher in nephrology. His research interests are focused on epidemiology, health services research, and clinical trials in acute and chronic kidney disease. Dr. Chertow is involved in research sponsored by the National Institutes of Health and has written numerous papers on end-stage renal disease, acute renal failure, nutrition, mineral metabolism, and the costs and outcomes of dialysis therapy. He is Co-Editor of Brenner and Rector’s The Kidney and serves on the editorial board of the Journal of the American Society of Nephrology (JASN). Dr. Chertow has designed and/or monitored several NIH- and industry-sponsored cohort studies and clinical trials in kidney disease, including CRIC, ATN, FHN, DAC, SPRINT, TREAT, ADVANCE and EVOLVE. In addition to his research and teaching activities, Dr. Chertow has an active clinical practice, focused on inpatient and outpatient nephrology care.

Meet the competitors for the Renal Replacement Therapy Bracket!

(1) Convective clearance versus (8) Diffusive clearance

Convective clearance

Convective clearance is back in the big dance, for the last few years we have seen convective clearance make a splash from the AKI conference in the form of CVVH, but after the recent conference realignment they now are showing up from the ESRD conference.

We all remember the epic battles that convective clearance used to wage with intermittent hemodialysis but this is an all new convective clearance wearing the online hemodialfiltration uniforms and it is ready to take on the all-time tournament leader, hemodialysis.

Convective clearance has long been known to improve middle molecule clearance, it does that by employing a highly porous filter and jacking up the ultrafiltration to around 30 liters in a single 4 hour dialysis session. In order to prevent turning the patient into a pile of salt, the technique requires replacing nearly all of that fluid.

Unlike dialysate, which flows past venous blood in the dialyzer, replacement fluid is infused directly into the veins, so not only does it need to be electrolyte balanced, it needs to be ultra-pure and sterile. Providing that ultra-pure replacement fluid, hundreds of liters a week for each patient was prohibitively expensive. The breakthrough that allows this to be used in the outpatient arena is a technique termed online purification. Online purification is the creation of sterile replacement fluid straight from the public water system in the dialysis unit. This is a major breakthrough.

However, this major breakthrough has not yet translated into breakaway results. In multiple randomized controlled trials hemodiafiltration has failed its primary end-point. Only in subgroup analysis has it been better than traditional hemodialysis. Then in 2013, the ESHOL study hit its primary end-point with a 30% risk of all-cause mortality. However, they did not do an intention-to-treat analysis and in a subsequent meta-analysis, no signal was found for improved all-cause mortality, non-fatal cardiovascular events or hospitalization, but there was a modest reduction in cardiovascular mortality.

Diffusive clearance

Diffusive clearance is a John Wooden lead UCLA. This dominant technique has been extending and saving lives since Kolff first used it on people during World War 2. It’s hard to imagine a NephMadness without a diffusive clearance entry.

How do they look this year? Well despite interesting results with convective clearance and new pushes to increase peritoneal dialysis, standard diffusive clearance hemodialysis is still being used by 92% of all Americans with ESRD. But most importantly hemodialysis keeps innovating. When the Frequent Hemodialysis Network published their original study on 6-times per week versus 3-times per week study, the dialysis nephrology community practically snored. The reason was that the study was not powered to show a mortality benefit. The study couldn’t answer the questions nephrologists and patients were asking about 6-days-a-week dialysis. Well, better late than never. At this year’s Kidney Week the FHN crew published an abstract with follow-up data. After an average follow-up of 3.7 years, the trends to improved survival with 6-days a week dialysis is now significant with a HR of 0.54.

Data from FHN abstract (see abstract FR-PO342 in Kidney Week 2013 abstract supplement).

(6) Residual Renal Function vs (3) Buttonhole Technique

Residual Renal Function

Residual renal function is like a Tarkanian lead UNLV team, they a super successful but they can’t get any respect. Win 30+ games in a season and people complain about a weak schedule. They are the Rodney Dangerfield of dialysis. This critical factor probably drives more survival outcomes than we care to admit and is specifically excluded from CMS Quality Incentive Program. Peritoneal dialysis patients do get to include residual renal function.

Here is what the Joseph Vassalotti, chief medical officer of the NKF, had to say about the lack of RRT in CMS plans:

Nonetheless, we are disappointed that residual renal function is not included in the calculation of hemodialysis Kt/V as some patients may have residual renal function that, in combination with dialysis, provides an adequate clearance for uremic toxins. Excluding residual renal function may lead to more aggressive (i.e. longer) dialysis prescriptions to meet the adequacy target.

Similar concerns were raised by Andrew Howard and Klemens Meyer, President Elect and President of the ESRD Networks:

The requirement to exclude residual renal function from reported Kt/V presents those facilities which choose to measure residual renal function with a dilemma: either accept a QIP penalty for supposedly (but not really) inadequate dialysis, or coerce the patient to accept a medically unnecessary prolongation of treatment time. This hardly sounds like patient-centered care, and we suggest that as written, the proposed Rule fails fairly to answer the question “How did the patient do?”

Residual renal function improves numerous patient factors including:

• lowers B2 microglobulin
• lowers potassium
• lowers aluminum levels
• raises bicarbonate level
• improves phosphate balance

But maybe Chandna and Farrington put it best when they wrote:

There is no logic in advocating aggressive measures to preserve RRF the day before dialysis initiation and ignoring RRF the following day. Likewise it is reasonable to question the practice of prescribing the same dose of dialysis soon after initiation—when many patients have considerable RRF—and to patients many years down the line—when RRF has long gone.

The benefits of residual renal function should be maximized and dialysis units incentivized to do this. DOPPS has shown improved RRF by using diuretics, this needs to be verified prospectively but these types of investigations won’t be done if the quality police ignore RRF.

Buttonhole Technique

Buttonhole cannulation is like a Brad Stevens-less Butler, a once high-flying mid-major, now living through some tough times. Buttonhole cannulation is a method for accessing AV fistulas for hemodialysis. The access needle is placed in the same location for every dialysis session, so that after a few weeks scar tissue forms a track. The track can then be accessed with blunt needles. It changes dialysis needle placement from a needlestick to something more similar to putting in a pair of earrings.

The buttonhole technique has a number of applications but the place where it was most appreciated was with home hemodialysis. The buttonhole technique is a way to greatly reduce the anxiety of accessing a fistula. It is not an exaggeration to say that much of the recent success of home hemodialysis was in part due to the re-emergence of the buttonhole technique.

However in January of 2014, Muir et al published data from a home dialysis cohort and did a systematic review of the literature and found an increased rate of infections with the buttonhole technique compared to the traditional sharp needle or rope ladder technique. Fifteen infections with buttonhole versus 2 with rope ladder. The systematic review of 15 studies (all published since 2007) likewise found a three-fold increase in  infection risk with the buttonhole technique. Though, this was not significant in the four RCTs (P=0.07), it did reach significance in the observational (P=0.0005) and the before-and-after studies (P<0.001). The discussion remarked that even the higher rate of infection found with the buttonhole technique was still one fourth the rate seen with tunneled venous catheters.

Nephrology is waking up to the trade-offs that seem to be inherent in buttonhole cannulation, the signal across numerous studies points to increased infection. Whether this can be improved with better aseptic technique or use of mupirocin antibiotic creams has yet to be determined.

(4) Urgent Start Peritoneal Dialysis vs (5) Fistula First Campaign

Urgent Start Peritoneal Dialysis

Acute peritoneal dialysis (PD) is a scrappy Rick Pitino inspired team. While they may not be running a full court press defense, they are re-writing some of the oral tradition of dialysis. Patients that present to the hospital with severe renal failure in need of immediate dialysis have always been directed to hemodialysis. As described by Ghaffari in AJKD, the newest innovation in peritoneal dialysis is the realization that with special consideration patents can start peritoneal dialysis almost immediately after having a PD catheter placed. This requires careful attention to the peritoneal volume and patients need to remain prone while their bellies are full of dialysate. But they can get early clearance and may never need to be exposed to a tunneled venous catheter.

This is changing the rules of PD. Patients that in the past who show up without previous CKD care were often classified as too irresponsible to do the self-care needed for PD. However, we are finding that a lot of these patients who start dialysis via acute PD stay with the modality for years. It is an innovative way to get incident dialysis patients to consider PD.

Fistula First Campaign

The mortality of patients receiving dialysis in the United States is worse than many other countries. Numerous theories and explanations have been put forth to explain this gap but one fact that was always inescapable was the low rate of fistulas and high rate of AV grafts/catheters found in the US. In 2003 CMS, the ESRD Networks, and other stakeholders initiated a National Vascular Access Improvement Initiative. The goal was to meet the current KDOQI target of 50% incident patients and 40% prevalent patients using fistulas. The program has been successful in moving patients from grafts to fistulas but the worst access of all, catheters, has not fallen, indicating additional work to be done. There is some data indicating that the increased focus on fistulas, with their finicky maturation rate, means that patients are relying on catheters for longer periods of time waiting for the fistula to mature (see Lok CJASN).

(2) DreamRCT ESRD versus (7) DreamRCT AKI

A DreamRCT is a thought experiment where people imagine what is the most important question in nephrology and then design an hypothetical RCT to answer the question. This next pairing pits two DreamRCTs against each other.

DreamRCT ESRD
(Chronic Hemodialysis versus Peritoneal Dialysis RCT)

This DreamRCT is whether Peritoneal Dialysis or Hemodialysis is the better modality for ESRD. Forever nephrologists have been torn on which modality was better PD or HD. This is a civil war in the field of nephrology. Truly brother versus brother.

The tragedy of this schism is that this is an answerable question. You could run a trial that answers this question once and for all.

• Is PD better than HD?
• Is that advantage durable?
• Does it last only as long as there is residual renal function or is this a durable effect?

And don’t forget the stakes. Hemodilaysis costs were $71,889 per patient per year in the U.S. compared to only $53,327 for those on peritoneal dialysis. Unfortunately, instead of a randomized controlled trial to shine the light of truth we are left with retrospective studies and USRDS statistics to wade through.

Attempts to randomize people to either modalities have been hampered by patient preference, people are hesitant to let something as big as modality choice be left to randomization. The Netherlands attempted to do this in a multi-center trial of 38 sites but after interviewing 773 people they could only entice 38 to consent to be randomized to HD or PD. The study is clearly underpowered and would be ignorable if the results were not so tantalizing. There was no difference in quality of life after one year (the primary end point) with a trend leaning toward HD. However, the 5-year survival data shows a relative risk of 3.8 for HD. Imagine, telling people that they could choose peritoneal or hemodialysis, but if they choose hemodialysis they will have nearly a four times higher risk of death in the next five years. To put this in perspective a permacath has a RR of 3.0 compared to a fistula. If this difference held up in a trial of significant size, it’s hard to believe it would do anything short of rewrite the landscape for incident dialysis patients.

However, beyond that one attempt to randomize patients, we are left to wade through retrospective data. In 2012, NDT published a large comparison of HD and PD among Canadians. From the discussion:

…comparing PD versus HD over time and by calendar cohort period showed that for the most recent cohort of 2001–04, patients receiving PD were associated with significantly better survival during the first 2 years of dialysis and that long-term survival (3– 5 years) was similar for PD and HD patients.

This survival advantage for PD does not necessarily apply to patients with diabetes. The Canadian trial found increased mortality hazard for women with diabetes that increased as the patients aged:

When overall survival was compared specifically for males and females, mortality was significantly higher for PD in both genders for patients with diabetes.

Unfortunately, one of the best done studies, a matched cohort trial (CHOICE Trial) found mortality benefit for HD.

Trying to make sense of the retrospective and observational data is like trying to trace the origin of a single noodle in a bowl of spaghetti. We should throw-up our hands, declare equipoise and get to the business of doing a randomized controlled trial.

The long held claim that is impossible to randomize patients to PD versus HD is untenable in a world with patients being randomized to brain surgery or sham brainsurgery, CABG or catheterization, and home hemodialysis or traditional in-center dialysis.

DreamRCT Acute Kidney Injury
(Intermittent Hemodialysis versus Continuous Venovenous Hemodialysis in AKI)

Intermittent versus continuous therapies is a rivalry as deep as Syracuse versus Georgetown or Kentucky versus Louisville. These guys hate each other. The situation in acute kidney disease is also completely different from PD versus HD, because in AKI we a have head to head data from randomized controlled trials and still no clear winner.

Mehta did one of the early trials comparing the modalities and he successfully randomized 166 patients in a multicenter trial in California, but someone slipped him some loaded dice because the randomization wasn’t balanced and the CRT group had higher APACHE-3 scores (P<0.045) and more liver failure (P<0.05). After that Table 1. failure, the results understandably showed increased ICU mortality (59.5% for CRT and 41.5% for IHD, P<0.02) and hospital mortality (65.5 for CRT and 47.6% for IHD, P<0.02) for continuous treatment. Using logistic regression to adjust for imbalances in group assignments, eliminated the increased danger of death with CRT.

Photo credit: Christopher Johnson.

The largest trial of IHD versus CRT was done by the French, the Tony Parker of RCTs. This multi-center trial randomized 360 patients to one of these two modalities and found no difference in 60-day mortality. 32% with intermittent and 33% with CRT.

A Cochrane Systematic Review was unable to find much benefit from CRT:

• In-hospital mortality (RR 1.01; 95% CI, 0.92-1.12)
• ICU mortality (RR 1.06; 95% CI, 0.90-1.26)
• number of surviving patients not requiring RRT (RR 0.99; 95% CI, 0.92-1.07)
• hemodynamic instability (RR 0.48; 95% CI, 0.10-2.28)
• hypotension (RR 0.92; 95% CI, 0.72-1.16)
• need for escalation of pressor therapy (RR 0.53; 95% CI, 0.26-1.08)

Though patients on CRRT were likely to have significantly higher mean arterial pressure (MD 5.35; 95% CI, 1.41-9.29) at the expense of higher risk of clotting dialysis filters (RR, 8.50; 95% CI, 1.14-63.33).

These are two equally matched powerhouses.

-Written and Edited by Dr. Joel Topf

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