Optimizing Therapeutic Options in Acute Renal Failure—An Ever Elusive Goal

The main therapeutic intervention for treatment of acute renal failure (ARF), extracorporeal renal replacement therapy (RRT) was introduced over half a century ago. RRT has changed the natural history of this disorder from a devastating condition that almost invariably led to the patient’s demise, to a manageable complication. Unfortunately, further improvement in survival rates among patients with ARF have at best been incremental, with mortality rates remaining unacceptably high (13).

Optimization of RRT carries the promise of improving clinical outcomes. Several treatment characteristics have been the subject of clinical investigations, including RRT intensity and type of modality. Two recently published trials addressed dialysis intensity and were unprecedented in scale and quality to any previously published work related to ARF (4,5). Unfortunately, the results of these trials were negative, finding no improvement in survival with higher treatment intensity. Previous, smaller scale trials addressing questions of modality and timing were similarly unrevealing. In addition to understanding the reasons why these characteristics of RRT seemingly have no effect on the survival of patients with ARF, this brief review raises the question of timing of dialysis as a new frontier with the potential for substantially improving the outcome of patients with ARF and for advancing the field of critical care nephrology further.

Intensity of RRT

It is logical to assume that increasing the intensity or dose of therapy would improve outcome in patients with ARF, i.e., the more therapy is administered, the better the correction of electrolyte and acid base disturbances, as well as the control of extracellular fluid volume and removal of uremic retention solutes, which in turn, leads to improved outcomes. However, it has been difficult, if not impossible, to demonstrate such a cause-and-effect relationship.

Several small, single-center studies on this topic have reported conflicting results and great heterogeneity of patient population, RRT modality, and design (611). Moreover, to date, there are no well-established and validated methods to measure intensity of RRT in ARF. Clearly, well designed and executed, adequately powered multicenter, randomized controlled trials have been lacking until two such trials were recently published demonstrating no measurable benefit in the higher intensity treatment arms (4,5). Despite these negative results, it has recently been argued that tools for quality assurance and performance improvement should be adopted for RRT rendered to patients with ARF, to ensure that the therapy delivered is at least as intensive as that provided in the lower-intensity groups of these two trials (12). It is important to note, however, that the minimal effective dose of RRT required to optimize survival in ARF is not yet known.

Continuous RRT (CRRT) versus intermittent RRT (IRRT)

The importance of CRRT as a modality for the treatment of critically ill patients with ARF is presented in detail by Tolwani in this issue. (see page 12). CRRT has become popular among nephrologists and intensivists due to its superior tolerability and capacity for volume and solute control, especially in critically ill patients with circulatory compromise. CRRT requires high resource and personnel utilization and there is a high mortality in patients chosen to receive CRRT. Comparing in a controlled fashion the effects of CRRT versus IRRT on mortality in ARF would be helpful. This question of course, as simple as it may seem, has been difficult to answer, because patients who typically require CRRT, and therefore are set to benefit most from it, are those who cannot tolerate IRRT, namely the hemodynamically unstable, making it impossible to randomize such patients to IRRT. On the other hand, patients who are able to tolerate either of the modalities, and thus would be good candidates for randomization, are not likely to benefit from CRRT, which is more invasive and more prone to untoward effects than IRRT. This dilemma is underscored by the lack of a mortality benefit for CRRT compared with IRRT in prospective randomized controlled trials as discussed by Tolwani in this issue.

In summary, CRRT, once a promising new method that allowed for the first time the administration of effective RRT and correction of metabolic and volume derangements in the most severely ill, did not prove superior to IRRT in direct comparison. However, CRRT will continue to have an important place in the treatment armamentarium for critically ill patients in whom IRRT is not an option.

Timing of RRT

Timely institution of RRT in ARF is fundamental to achieving treatment goals, namely solute clearance and fluid balance, while awaiting recovery of kidney function. Currently indisputable indications for RRT include persistent hyperkalemia, severe metabolic acidosis, and hypervolemia unresponsive to conservative measures; uremic serositis; bleeding diathesis; and severe encephalopathy (13). Beyond these indications and when azotemia is the sole abnormality, it is unclear when RRT should be started. “Early” or “prophylactic” RRT historically described the initiation of dialysis therapy before nitrogenous waste products reached some arbitrary predefined “critical” blood value, regardless of other indications. Older reports suggested that early initiation of RRT might improve survival (14,15), but this has not been confirmed in recent years.

We performed a comprehensive review of all available data on this topic by conducting a systematic review and meta-analysis to examine the effect of early initiation of RRT on survival (16). Again, the heterogeneity of the individual studies was formidable. They included randomized controlled trials, trials with sequential treatment assignment, and prospective and retrospective comparative cohort studies. In addition, the studies spanned more than four decades. In the primary analysis, which included four randomized controlled trials and one quasi-randomized controlled trial totaling 270 patients, early RRT was associated with a 36 percent mortality risk reduction (relative risk = 0.64; 95% confidence interval = 0.40, 1.05; p = 0.08). In a secondary, more inclusive analysis comprising 18 comparative cohort studies and totaling 2108 patients, early RRT was associated with a 28 percent mortality risk reduction (relative risk = 0.72; 95% confidence interval = 0.64, 0.82; p < 0.001).

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This systematic review suggested that early institution of RRT might have a beneficial effect on survival of patients with ARF. Besides the design and methodological concerns of the studies included, the most commonly used criterion for “early” versus “late” initiation of RRT was an arbitrary cutoff of blood levels of retention solutes, rather than an objective time variable from onset of renal failure to RRT. This represents a fundamental design flaw since not only the time, but also the velocity of uremic retention solute accumulation such as urea, related in part to the degree of protein catabolism, determine its blood level.

Overall, these findings require confirmation by a large multicenter randomized controlled trial primarily designed to assess the effect of timing of RRT on survival in ARF. A trial designed to answer this question should be adequately powered. If one conservatively assumes an overall hospital mortality rate of 25 percent in patients with ARF regardless of dialysis requirement (3,17) and a hypothesized 36 percent mortality risk reduction derived from the aforementioned meta-analysis (16), a sample size of approximately 1100 would be required to achieve 90 percent power, which is a feasible goal. Much more thought and deliberation, however, must be spent on selecting the appropriate patient population and entry criteria. Clearly, an arbitrary cutoff value for urea or similar retention solutes will not suffice. Other measures—including novel urinary or blood markers conferring prognostic discrimination toward a prospective need for RRT—might be more valid inclusion criteria.

Finally, a large observational study to further characterize practice patterns and variation in RRT care internationally might help identify more robust criteria for timing of RRT, which in turn, might possibly help develop best practices of care. In summary, after completion and publication of two definitive, large-scale clinical trials addressing RRT intensity and modality in ARF, a case is made for the next “RRT frontier” that might promise improvement in outcomes, i.e., the timing of RRT initiation. Based on the results of a recent systematic review, we argue in favor of designing and carrying out a large-scale, definitive clinical trial on timing of RTT initiation in ARF, while avoiding potential pitfalls and study design flaws.

Notes

[1] Orfeas Liangos, MD, FASN, and Bertrand Jaber, MD, FASN, are with the Department of Medicine, Division of Nephrology, St. Elizabeth’s Medical Center, in Boston. Liangos is also with the Division of Nephrology, Klinikum Coburg, Coburg, Germany.

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