NephMadness 2014: Acute Kidney Injury Bracket

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PastedGraphic-5These competitors will surely challenge each fan’s loyalty to nephrology tradition for both seasoned professionals and those in their rookie years. Extra security has been brought in to ensure that game-time emotions are appropriately diuresed and kept under pH control especially for the international matchup of KDIGO vs KDOQI AKI guidelines, the potentially acidic battle between Saline and Balanced Solutions, and the playoff round of old (Traditional urinary indices) vs new techniques (Urinary biomarkers)  for diagnosing AKI. Not to be overlooked among all this controversy is the king of AKI, CIN (Contrast-Induced Nephropathy) that may very well prove to be too overwhelmingly nephrotoxic to be seriously challenged by any of the other teams.

Selection committee member for the Acute Kidney Injury Bracket:


Sarah Faubel, MD
Associate Professor of Medicine
University of Colorado Denver
Staff Physician at the Denver VA Medical Center

Dr. Faubel’s primary area of research is the distant organ effects of AKI in rodent models, particularly proinflammatory cytokine production and lung injury. Studies are focused on the generation and resolution of inflammation after AKI, with the view that dysregulated inflammation after AKI is a key driving force behind the deleterious systemic effects associated with AKI. Complications from the distant organ injury of AKI are now recognized as a potential mechanism for the increased mortality observed in patients with AKI.

Meet the competitors for the Acute Kidney Injury Bracket!

(1) Contrast Nephropathy vs (8) Remote Ischemic Preconditioning (RIPC)

When told that their first round opponent was Remote Ischemic Preconditioning (RIPC), Contrast-Induced AKI skeptically queried “who?” and started to make comments about who they would have to play in the second round. On paper, this looks like a complete blowout but there is a reason RIPC was chosen as a sleeper for the tournament. Employing a completely unique defensive strategy, RIPC has stunned opponents with their anti-oxidant and anti-inflammatory potential. Not impressed, Contrast Induced AKI predicted that their opponent will definitely need to R.I.P. after they experience the full nephrotoxic power of iodinated contrast. Could the overconfidence of Contrast-Induced AKI set them up for a first round upset?

Contrast Nephropathy

The #1 seed is well deserved by this team composed of an array of ionic and nonionic iodinated benzene ring derivatives. Relentlessly coming at you in waves of high, low, and iso osmolar boluses, the defenseless proximal tubule is no challenge for Contrast-Induced AKI. ATN magazine ranks Contrast-Induced AKI as the leading cause of hospital-acquired ATN for over 20 consecutive years. This team is offensively driven unleashing both intense renal cortical and medullary vasoconstriction as well as direct cellular injury.

Contrast-Induced AKI leaves a long lasting impact on its opponents who are rarely able to completely recover and perform back at their full capacity accompanied by an accelerated development of CKD in their future. Both short and long term mortality is markedly increased after Contrast-Induced AKI is present.

As a sign of its popularity, over 500 peer reviewed articles are written yearly about Contrast-Induced AKI. Molecular size, speed of toxic injury, and widespread exposure all make Contrast-Induced AKI a formidable and almost unbeatable team.

Remote Ischemic Preconditioning (RIPC)

RIPC was the last team to get into the tournament and was initially overlooked by every expert. Always playing with a hypoxic chip on their shoulders, RIPC knows there is a lot pressure on them to show they deserve to be in this bracket. RIPC utilizes a strategy never before seen in this tournament and first originated this unique game plan in 2006. The background for this approach is rooted in the classic chess gambit practice of sacrificing a pawn for later victory. RIPC is based on causing temporary remote ischemia of one organ to protect another.

Their technique is elegant yet simple: starting 2 hours before a potentially nephrotoxic event, intermittent upper arm ischemia is produced by 4 cycles of 5-min inflation of a blood pressure cuff to 200 mm Hg followed by 5 minutes of deflation. This novel procedure reduces oxidative stress by activating a variety of biochemical events including the phosphatidylinositol 3-kinase/Akt (PI3K-Akt) pathway. There may also be an anti-inflammatory component to the action of RIP but this is still not fully defined.

RIPC has been on a roll recently demonstrating significant renal protection against a variety of insults after coronary bypass surgery or abdominal aneurysm repair. Interestingly RIPC already played an early “friendly” scrimmage against Contrast-Induced AKI and shocked their opponents by pulling a stunning upset win by significantly reducing kidney injury.

RIPC knows it’s a heavy underdog, but like David and Goliath, sometimes victory can be achieved against a superior opponent by using a simple unexpected weapon such as a plain slingshot or in the case of RIPC a standard blood pressure cuff.

RIPC truly believes it will inflate its way to victory.

(3) U/A and Indices  vs  (6) AKI Biomarkers

This bracket is a classic first-round matchup of teams with completely opposite ideologies. On one side we have Urinary Indices: Traditional Way  that rely on the same game plan over and over again that has worked so well in the past no matter who the opponent is, as opposed to Urinary Indices: Modern Way who have developed a whole new game strategy based on more modern scientific techniques. Past vs Present! Is it finally time for Urinary Indices to enter the 21st century and retire the Traditional Way once and for all? Do years of Tradition prove to be too powerful to push aside just because they are considered to be old fashioned? It’s a toss-up!

U/A and Indices: Traditional Way

This team is well known to medical students, junior staff and senior staff of all specialties. The starting five consist of FENA, FEUREA, Urine Lytes, Granular casts and Urinalysis with Urine Osmolality and Specific Gravity coming off the bench for added diagnostic and scoring accuracy. In spite of the low salary for each player, the quick turnaround of the games and the widespread ease of ordering, critics have long argued that this team is getting on in years with no new players having been added for decades. More importantly, recent reviews have further questioned the “accepted” accuracy of these indices in predicting the severity and outcome of AKI.

Once considered to be the star player FENa has had a challenging time when faced against a team that uses diuretics, CKD, or heme pigment toxins. In addition, FEUrea has similarly slowed down over the years having a very difficult time in sensitivity (61%) and specificity (59%) in ICU patients.

These weaknesses have exposed this team and questioned the ability of Urinary Indices: Traditional Way to stay on top of the rankings in the workup of AKI. Nevertheless, Urinary Indices: Traditional Way continues to be a fan favorite and when they approach the bedside to their anthem “Tradition” from Fiddler on the Roof, even the most stoic critic will find themselves joining in and measuring along.

AKI Biomarkers: Modern Way

Embracing the recent breakthroughs in molecular and immune monitoring for tissue injury, this team is poised to go to the next level. Certainly not household names yet, this group of enzymes and cytokines have joined together to prove a worthy successor to the title of AKI champion. The current team consists of NGAL (Neutrophil Gelatinase Associated Lipocalcin), KIM-1 (kidney Injury Molecule 1), IL-18 (Interleukin 18), NAG (N-acetyl-β-D-glucosaminidase), and Cystatin C. More new players are being recruited regularly.

The team is primarily from the proximal tubule and have been shown to be particularly sensitive in the diagnosis of incipient AKI after radiocontrast exposure, surgery, sepsis, or kidney transplantation. In addition, these biomarkers have been shown to predict short and long term outcomes after AKI more accurately than the Traditional Way. The lack of widespread availability and defined normal parameters of this team has hindered their recognition and application by nephrologists. In addition, current KDIGO Guidelines have yet approved Urinary Indices: Modern Way as an accepted alternative or adjunct for the diagnosis of AKI over the Traditional Indices.

This is a team of limitless potential that may need more time to work together as a unit and a few more key players before it can compete at the highest level.

(4) Fluid Resuscitation: Normal Saline versus (5) Fluid Resuscitation: Balanced Solutions

These 2 teams are so closely matched that they differ only by a slight difference in pH, a few milliosmoles of tonicity, and a few milliequivalents of chloride. Each solution remains under the radar as a serious threat to win the AKI bracket but never underestimate the simple elegance and long lasting economic and survival benefit of successful fluid resuscitation in reducing the risk of AKI. Strong vocal advocates abound for each team and they remain undeterred in their loyalty. This game is going to go down to the last ml.

Fluid Resuscitation: Normal Saline

This team manages to hold its own even with just 2 players: Na and Cl. Somehow in spite of their small numbers they manage to fill the entire intravascular volume and put up a valiant fight to prevent hemodynamic and contrast-induced AKI. Promotional material handed out by the team point to the many peer-reviewed publications confirming successful pre-emptive deployment of Normal Saline in the prevention of AKI. Importantly the Saline vs Albumin Fluid Evaluation (SAFE) study confirmed the benefit and cost-effectiveness of Normal Saline compared to albumin in preventing AKI. In addition, compared to colloids such as hydroxyethyl starch (HES), Normal saline has again prevailed as a safe and effective option for fluid resuscitation. Finally, the KDIGO AKI guidelines recommend Normal Saline as the first option for volume expansion basically labeling it as the MVP (most valuable player) of fluid replacement.

In spite of this string of victories and awards, critics continue to call Normal Saline an “unbalanced solution” that causes excessive hyperchloremia and metabolic acidosis. They point to research studies that show direct injury from hyperchloremia to the vascular endothelium that when coupled with the iatrogenic lowering of the pH leads to disruption of the renal microvasculature and worsening AKI. Finally, Fluid Resuscitation: Normal Saline has been accused of being overly aggressive and not knowing when enough is enough. Overzealous team effort has led to excessive volume expansion and increased mortality.

Fluid Resuscitation: Normal Saline shrugs off these comments and has only one thing to say to its critics: Bring it on!

Fluid Resuscitation: Balanced Solutions

Respect! All this team is looking for is R-E-S-P-E-C-T. This is a well “balanced” squad that isotonically achieves volume normalization without altering systemic pH or the electrolyte concentration. Each member of the team was chosen specifically to maintain the Na, Cl, HCO3 and potassium concentration with the added benefit of calcium and magnesium control as a bonus option.

This team has labored in the shadow of Fluid Resuscitation: Normal Saline for years and has yet to breakthrough into the mainstream. In order to change the prescribing patterns of physicians, Balanced Solutions knows that they will need concrete evidence and a blockbuster study to support their cause. So far things are looking promising at the bench research level. Compared to their arch nemesis Normal Saline, Balanced Solutions resulted in improved renal blood flow and a reduced risk of AKI. Clinically, even better news is on the horizon as Balanced Solutions own an early victory in comparison with Normal Saline in critically ill patients for the prevention of AKI.

(2) KDIGO: AKI Definition vs (7) KDOQI: AKI Definition

Front and center is an international battle of definitions and recommendations between KDIGO:AKI and KDOQI:AKI. Nationalism has always played an important role in the Olympics and this competitive spirit has now extended itself to the field of AKI. Representing the international community in one corner is the widely popular KDIGO:AKI, carrying the hopes and dreams of thousands of nephrologists and primary care physicians to finally unify AKI like the Euro has unified Europe. Standing in the way of KDIGO and world domination is a team from the United States, KDOQI:AKI, representing the American way of dealing with AKI. No amount of diplomacy can prevent this battle from occurring. There will be only one winner.

KDIGO: AKI Definition

This is a powerhouse team that commands immediate respect. No other team is so well known just by its initials and boasts an international reputation – Kidney Disease Improving Global Outcomes: Acute Kidney Injury – KDIGO:AKI. Initially conceived in 2011, it took a whole year for a workgroup of 18 experts and an entire evidence review team from Tufts Medical Center to assemble the final 138 page product. No controlled trial or meta-analysis was ignored in the collation of 783 references spread out over 5 chapters, 23 tables and 17 figures. A new working classification of AKI, recommended evaluation strategies and clinical maneuvers for prevention of AKI have been detailed and supported by evidence-based analysis. This awe-inspiring compilation of 87 recommendations immediately intimidates every opponent whether at home or on the road.

KDIGO:AKI appears to have emerged as the AKI definition champion after overwhelming RIFLE and AKIN in the playoffs. Many of the players of both RIFLE and AKIN made their way to join KDIGO:AKI knowing that together they may be able to win it all!

KDOQI: AKI Definition

No stranger to international competition, the National Kidney Foundation has assembled an all-American team to challenge for the definition and evaluation of AKI title called the Kidney Disease Outcomes Quality Initiative (KDOQI). The gauntlet was thrown down against KDIGO:AKI at the opening press conference with KDOQI:AKI announcing “we question whether these staging criteria of AKI (by KDIGO) are currently appropriate to guide clinical management of adult patients.” As if that wasn’t enough to stir emotions, KDIGO went on to say “we believe that current data are inadequate to support the reliance on oliguria as a surrogate endpoint in clinical trials or in performance metrics.”

KDOQI:AKI places emphasis on the cause and duration of AKI as a major predictor of long-term outcome and does not believe patients should be individually treated based on the stage of AKI as per KDIGO.

KDOQI:AKI states that its sole mission is look out for U.S. citizens and that implementation of KDIGO:AKI will result in a “dramatic increase in unnecessary nephrology consultations” and inappropriate labels of AKI in hospitalized patients.

In total, KDOQI:AKI provides its 76 recommendations in a lean 23 pages with 164 references.  With chants of “USA, USA, USA” in the background, KDOQI:AKI could be the surprise dark horse of the tournament.

-Written and Edited by Dr. Warren Kupin

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