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Contrast Nephropathy vs Remote Ischemic Preconditioning (RIPC)

Winner: Contrast Nephropathy

Source of original image.

Contrast nephropathy took home the win in convincing fashion. Team Contrast Nephropathy, also known as the Cath Cowboys, came with a deadly one-two punch: contrast nephropathy is both common and lethal. Contrast nephropathy is sparking fear throughout the tournament and a hefty amount of research devoted to its prevention. This research is culminating with the ongoing PRESERVE trial, weighing in at over $23 million, it will enroll 8,680 patients to a 2×2 factorial design in order to determine whether NAC or sodium bicarbonate are any better than normal saline for the prevention of contrast nephropathy.

By far the most impressive part of the trial is the (relatively) hard-end point they will be using:

• primary: composite of 90-day mortality, need for dialysis, persistent decline in renal function
• secondary end-points: development of contrast induced nephropathy, 90-day hospitalization for acute coronary syndrome, heart failure or stroke, 90-day all-cause hospitalization, individual primary endpoints,
• tertiary endpoint: 1 year ESRD and mortality

This trial will become, by far, the largest randomized controlled clinical trial conducted in nephrology (recall that the very large ATN and RENAL trials enrolled 1,124 and 1,508 patients, respectively).

Despite the loss, remote ischemic pre-conditioning showed its potential. In a recent review, 7 studies with a total of 4,689 patients were studying the use of remote ischemic preconditioning for the prevention of AKI in adults or children undergoing cardiothoracic surgery.

Urinary indices versus biomarkers

Winner: Urinary indices

Probably the sloppiest game of the first round, traditional urinalysis and urinary indices eked out a win over, oh so trendy, biomarkers – yet both teams played poorly.

The biomarker team needs to learn the fundamental truth that there is no “I” in team. Pregame, the players touted their individual achievements all saying that they were the best – but when it came to game time, they just couldn’t work together and that led to their downfall.

Close analysis reveals that the individual biomarkers may have been over-hyped. Indeed, in one of the largest studies thus far, the best performing biomarker, urine IL-18, had only a sensitivity of 54% and a specificity of 82% in adults to predict AKI (Urine NGAL had a sensitivity of 46% and specificity of 82%; plasma NGAL with a sensitivity of 50% and specificity of 82%).

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Dick Vitale was adamant, that for biomarkers to get over the hump (especially NGAL, IL-18, KIM-1, L-FABP, Cystatin C, and urine enzymes) “Baby! They need to learn to work together as a team!” Some are good post-cardiac surgery, some are good early, some are good later, and some are good in sepsis – but one biomarker isn’t going to be able to carry the team. Once they start playing together, the potential to predict and accurately stage AKI might finally be realized.

Despite the loss, there is great hope and optimism for the future for biomarkers. The red-shirt freshman, cell cycle arrest markers, will play next year and the scouting report looks good for these markers to predict AKI in patients admitted to the intensive care unit; we wonder if the cell cycle arrest markers should try to get catchier names, though, as tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7) don’t go well in cheers.

The biomarkers also need to play in the right context. Similar to troponin only being checked when there is chest pain or suspicion for an MI, a similar “renal angina index” is being tested and developed to guide the clinical scenario in which measuring AKI biomarkers might be most useful.

The traditional team played as usual: many brilliant calls and many predictable mistakes. Urine sodium was low and correctly identified the pre-renal patient, but was also low in contrast-induced AKI and sepsis in whom balanced electrolyte solution resuscitation did not lead to improved kidney function. FeUrea worked in patients receiving diuretics, but had a poor performance in the ICU with a sensitivity of 63% and specificity of 54% (with a cutoff of 35%) (6). But, by sticking to what they know and dealing with what they didn’t know, they managed to pull off the win.

Despite the loss, remote ischemic pre-conditioning showed its potential. In a recent review, 7 studies with a total of 4,689 patients were studying the use of remote ischemic preconditioning for the prevention of AKI in adults or children undergoing cardiothoracic surgery.

Normal Saline vs Balanced solutions

Winner: Balanced solutions

It wasn’t even close. Balanced electrolyte solutions trounced normal saline in a game that had fans bored and even booing the poor performance of normal saline at the end. The distaste for normal saline was intense. Said one fan: “normal saline isn’t even normal!  154 mEq/L of sodium and 154 mEq/L of chloride – who ever heard of a serum chloride of 154 mEq/L? That’s 48 mEq/L off! They’re just a bunch of liars.”

Being associated with hyperchloremic metabolic acidosis and AKI in patients were just two of the major downfalls of “normal” saline that lead to its loss. Sealing the deal was a study from the near future (publication date, April 2014) comparing balanced solution and normal saline for resuscitation in rats with sepsis; compared to balanced electrolyte solution, rats resuscitated with normal saline had increased serum chloride, decreased pH, increased AKI severity, and increased mortality.

Despite the victory here, normal saline remains the most widely used isotonic crystalloid in North America. One wonders, about the chances of balanced electrolyte solutions moving forward in the tournament, given that a head to head comparison of balanced solutions and saline has not been performed in patients. DreamRCT anyone?

AKI Guidelines: KDIGO versus KDOQI

Winner: KDOQI

In the closest match of the AKI bracket, KDOQI guidelines edged out KDIGO guidelines. Despite the US homefield advantage, KDOQI was the underdog. Some had predicted that with its thin 23 pages that KDOQI would be no match for the behemoth KDIGO’s 138 pages and international experience. In many ways, though, KDOQI was playing with the same play book as KDIGO – essentially copying and agreeing with most of their plays, but adding just enough improvements to get the win. Notably, KDOQI agreed with:

1. all of the level 1 recommendations for the prevention and treatment of AKI (KDIGO chapter 3)
2. the majority of recommendations for contrast-induced AKI (KDIGO chapter 4)
3. all of the level 1 recommendations for dialysis management in AKI (KDIGO chapter 5)

The winning formula for KDOQI relied on a number of key plays at the end, especially exploiting the KDIGO trip up regarding the appropriate dose of intermittent dialysis. In recommendation 5.8.3 (the second to last recommendation of the document), KDIGO states “We recommend delivering at least a Kt/V of 3.9 per week when using intermittent or extended RRT in AKI. (Level 1A)”. Of course, everyone knows what they meant – that dialysis dose should be a Kt/V of 1.3 per treatment in AKI patients receiving thrice weekly hemodialysis, and KDOQI agreed with this recommendation. But KDOQI called them out on how they said it by noting that “3.9 is based on the arithmetic sum of the dose per individual treatment. Kinetic modeling suggests that this is erroneous and that prescription of intermittent hemodialysis to provide a Kt/V of 1.3 three time per week or a Kt/V 0.65 six times per week are not equivalent.” This technical foul was one of the factors that played into the win for KDOQI, even though both groups essentially agree on this issue and also agree that delivered dose of dialysis should be assessed frequently in AKI since delivered dose is typically lower than prescribed dose.

Sealing the win were KDOQI’s recommendations about the definition of AKI. KDOQI’s rejected the use of urine output to define AKI and they rejected KDIGO’s use of weight based definition of AKI. Using KDIGO’s formula would mean that a urine output of 40 mL/hr in a 90 kg patient for 12 hours, 480 mL, would be classified as stage 2 AKI. Lastly, KDOQI rejected the addition of yet another definition, namely: acute kidney disease, to bridge the nomenclature between AKI (48 hours or so) and CKD (3 months).

Overall, however, these teams were extremely well matched and the game was conducted with dignity, respect, and poise. “We are really very similar teams” noted one member of the KDIGO team humbling accepting the unexpected defeat.

Moving forward – the KDOQI AKI recommendations are looking pretty tough to beat. Their lean and mean team covers the range of evidence for defining, preventing, and treating AKI. Given that AKI is the most common reason for inpatient nephrology consultation in the US, KDOQI is looking unbeatable.

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