Precious Bodily Fluids

Everything I learned in fellowship has turned out wrong. When I was a fellow I was taught:

• Higher Kt/V were beneficial for patients
• Increasing the hemoglobin reduced LVH and improved outcomes in CKD
• Using non-calcium based binders saved lives
• and most importantly: increasing the dose of dialysis in AKI improved survival

The last point was an area that was emphasized in my education. I heard Dr. Murray spend so much time going over the preliminary evidence that I was honed to proselytize the gospel of early and often dialysis for acute kidney injury. I loved working with Murray, he’s a great speaker, a great teacher and the only man with more board certifications than years in middle school (internal medicine, nephrology, critical care, clinical pharmacology).

Since finishing fellowship it has been humbling watching each of these truths fall to the blade of the RCT (though I still believe that calcium based binders are harmful).

The results of the ATN Trial this past summer has been especially heartfelt because I was so invested in the outcome. I had argued and fought so many times to get an access and initiate dialysis, to get an extra-treatment, all this time being smugly self confident that I was helping the patient. Confident that I was fighting the good fight. Ughh.

So here it is, a review of the article that kicked me in the chest…
The objective was to determine if more intensive dialysis for acute kidney injury would improve survival in critically ill people. Unique to this trial, the protocol allowed patients to get either conventional hemodialysis or hemofiltration depending on the hemodynamic status of the patient at any time during the trial. This innovation allows the trial to better track actual practice. Additionally, it allows the trial to get past the eternal debate of which modality is better, and answer the question of what dose to target regardless of the modality.

The study was conducted from 2003 to 2007.

The trial was run at 27 institutions.

Enrollment criteria:

• Critically ill adult
• Age: 18 or older
• Renal failure plus at least one other organ system failure or sepsis

Patients who were hemodynamically stable were provided hemodialysis (prescribed Kt/V 1.2-1.4). If they were unstable, CVVH or SLED was provided. The decision between CVVH and SLED was determined by individual site preference.

Patients were randomized to one of two dosing schemes:

Less-intensive strategy:

• Stable: Intermittent hemodialysis: 3 days a week effluent
• Unstable: Continuous therapy: effluent of 20 mL/kg/hr

Intensive strategy:

• Stable: Intermittent hemodialysis: 6 days a week effluent
• Unstable: Continuous therapy: effluent of 35 mL/kg/hr

These definitions for dose come from Ronco’s paper (continuous therapy) and Schiffl’s paper (intermittent therapy) two studies which are (were?) frequently invoked as support for high dose dialysis in acute kidney injury.

Dialysis was continued until recovery of renal function, discharge from the ICU or 28-days of therapy or death. Recovery of renal function was defined by 6-hour CrCl of >12 mL/min and investigator discretion or >20 mL/min.

Primary Endpoint: All-cause mortality at day 60.

Secondary endpoints:

• In-hospital death
• Recovery of renal function (CrCl>20). Recovery was defined as complete if Cr was <0.5>0.5 over the baseline creatinine.
• Duration of renal replacement therapy
• Dialysis free at 60 days
• Duration of ICU stay
• Return to previous home at day 60.

Power analysis

• Estimated mortality with less-intensive strategy 55%
• Estimated mortality with intensive strategy 45%

The authors estimated 10% loss to follow-up and all patients lost were assigned to “alive” for analysis. 90% power with a sample size of 1164.

Enrollment was below the power analysis goal of 1164 at 1124 but the study had better retention with 29 being lost for various reasons and 5 being lost and analyzed as “alive.” The power analysis anticipated 112 people being lost.

The all important table 1. shows a cohort that looks similar to the patients I take care of. 60% sepsis and 80% ventilated. Appache 26. All and all, a sick cohort.

The protocol was adhered to extremely well with extra treatments occurring on 0.5% of days in the high dose group and .5% of days with less-intensive strategy. Missed treatments occurred on 1.9% of days in the intensive strategy and 1.1% in less-intensive strategy. Surprisingly, the delivered dose of dialysis with intermittent therapy was a Kt/V of 1.3, right in the middle of the prescribed target. ICU patients are classically difficult to dialyze and previous analysis of delivered dose have shown it to lag well behind prescribed dose.

With continuous therapy the delivered dose like-wise correlated well with prescribed dose: 36.2 mL/kg with intensive strategy and 21.5 mL/kg with less-intensive strategy.

Primary outcome: 53.6% 60-day mortality with less-intensive strategy and 51.5% mortality with intensive strategy (p=0.47).

Secondary outcomes:

• In-hospital mortality: 48.0% less-intensive strategy, 51.2% intensive strategy
• Complete recovery of renal function (day 28): 18.4% less-intensive strategy, 15.4% intensive strategy
• Return to home by day 60: 16.4% less-intensive strategy, 15.7% intensive strategy

Complications: Patients on the intensive strategy required vasopressor support during renal-replacement therapy more often, 14.4% vs 10.0% (p=0.02) and required interventions for hypotension more often, 37.7% vs 30.0% (p=0.006). However, in intermittent dialysis both groups reported similar rates of dialysis associated hypotension 18.5% with intensive vs 18.0% with less-intensive) and similar drops in blood pressure (MAP from 86 to 75 with intensive and from 86 to 74 with less-intensive). The increase in dialysis associated events maybe related to the increased frequency of dialysis (more exposures to dialysis) with intensive strategy.

Hypophosphatemia (17.6% vs 10.9%, p=0.001) and hypokalemia (7.5% vs 4.5%, p=0.03) were both more common with intensive therapy than with less-intensive therapy.

The editorial by Bonventre that was published with the article was okay. I would re-direct interested readers to the Hume, et al. editorial in AJKD which was better.

Some points from the Bonventre article include:

• Increased numbers of men in the study
• Lack of CKD patients
• Questions about the changing of modalities allowed by the protocol
• Increased amount of SLED in the intensive therapy group compared to the less-intensive strategy

Some choice quotations from the Hume article:

This report currently should be viewed as the definitive study defining dialysis dosing in critically ill patients with AKI.

During the maintenance phase of AKI, while hemodialysis/hemofiltration techniques are being utilized, the patient dies from multi-organ failure while in exquisite electrolyte and fluid balance.

Our group has focused on 2 major areas of evaluation. The first is the recognition that current renal substitution therapy only provides the small-solute clearance function of the kidney but not the metabolic and endocrine functions of the kidney. Similar to the clinical evidence that kidney transplantation markedly prolongs survival and improves health related quality of life compared to dialysis, the replacement of renal parenchymal cell functions in AKI may change the natural history of this disorder.