Which Patients Benefit from Initiation of Dialysis for AKI?

The decision to start dialysis is a clinical one that is influenced by several factors, including assessment of fluid, electrolyte, and metabolic status. There is little information from clinical trials to guide this decision. Traditional indications for dialysis (hyperkalemia, metabolic acidosis, and volume overload or overt uremic signs) are late complications of AKI. More commonly, dialysis is started preemptively, once AKI is established and complications are deemed unavoidable. The evolving paradigm of dialysis as “renal support” rather than “renal replacement” has led to wide variations in practice. It is difficult to separate the issue of which patients benefit from dialysis from the issue of when to dialyze a patient with AKI. There is a growing body of observational evidence suggesting a mortality benefit associated with “earlier” initiation of dialysis in patients with AKI, although early initiation remains ill defined (1,2). To date, there have been no adequately powered appropriately designed randomized trials that have evaluated early versus late initiation of dialysis for AKI; however, early initiation has now become the standard of care. Two recent Canadian multicenter observational studies of critically ill patients revealed that dialysis is now routinely initiated within 2 days of admission to the hospital (3,4). However, because the decision to initiate dialysis is a subjective one, observational studies in this area are subject to confounding by indication—there may be fundamental differences in participants who were offered early dialysis compared with those who were not. An additional factor to consider is that the vast majority of observational studies restricted their analyses to patients who received dialysis. By limiting the comparison to patients treated early or late, the studies do not account for the large number of patients who meet “criteria” for early treatment but never undergo dialysis. Initiation of therapy in patients that would have spontaneously recovered may unnecessarily expose them to RRT and its attendant risks. In this issue of CJASN, Wilson et al. (5) report on the benefit of dialysis initiation in a large cohort of patients with severe AKI using propensity-matched analysis. The authors generated a time-varying propensity score using a combination of clinical, demographic, and laboratory data to represent the daily probability of dialysis initiation. Using this score, nondialyzed patients with AKI (n=545) were then matched and compared with dialyzed patients. No significant difference in mortality was observed between groups that did and did not receive dialysis (mortality hazard ratio for dialyzed patients, 1.01; 95% confidence interval [95% CI], 0.85 to 1.21; P=0.89). As has been noted in other observational studies, participants dialyzed at higher serum creatinine levels had better outcomes than those dialyzed at low serum creatinine levels (3). Furthermore, serum creatinine was found to modify the effect of dialysis on mortality. Dialysis was associated with greater mortality at low serum creatinine levels, whereas dialysis was associated with lower mortality at high serum creatinine levels. The authors speculate that these findings could be explained by metabolic differences between the patients with low creatinine compared with patients with high creatinine. Patients with higher catabolic rates and/or greater muscle mass (ergo healthier) may have higher creatinine levels during an AKI episode and therefore have greater benefit from dialysis. Although the findings of this study are similar to other observational studies, the novel aspects of this analysis are the inclusion of nondialyzed patients in the study cohort and the analytical method. These address much of the criticism leveled at other observational studies of dialysis initiation and allow comparison of early and late dialysis initiation with conservatively managed AKI. However, the robustness of the study results relies on the degree of matching between dialyzed and nondialyzed patients. Although the authors should be commended for the rigorous methodology underlying this analysis, it has several significant limitations that merit further discussion. The decision to offer or initiate dialysis is a complex one, informed by laboratory data, clinical data, as well as physician judgment. For example, the recently published Kidney Disease: Improving Global Outcomes AKI guidelines suggest stage-based management of AKI, with consideration of RRT in patients with stage 2 AKI or greater. However, in practice, the vast majority of these patients will not be dialyzed (6). Beyond serum creatinine, what factors do physicians consider when making a decision to dialyze? The Canadian AKI investigators consortium surveyed 180 intensivists and nephrologists across Canada to determine what clinical and biochemical factors were important in determining when to initiate dialysis (7). The survey, which included a prioritization exercise as well as several clinical scenarios, identified serum potassium and severity of pulmonary edema as the two most important factors in the decision making process, with the most common reason for initiation of dialysis being “worsened oxygenation.” RRT was also less likely to be started if the patients were responsive to diuretics. Moreover, nephrologists were less influenced by biochemical parameters and were more likely to initiate early RRT based on the clinical variables of oliguria, pulmonary, and peripheral edema. A second international survey of 170 nephrologists by Thakar et al. found similar results (8). In all presented clinical scenarios, serum potassium, oxygenation, and urine output were identified as the most influential factors in clinical decision making around dialysis initiation. The survey authors additionally found that early dialysis, defined as initiation within 24 hours, was most likely to be initiated in patients with the highest severity of illness scores, a population unlikely to experience a survival benefit with dialysis treatment. How well were these factors accounted for in the propensity analysis? The final propensity score model matched patients on 32 variables; however, urine output or other measures of fluid overload (pulmonary edema, fluid balance) were not included because this information was only available in a limited subset of patients. Unfortunately, the exclusion of this information leads to the possibility of residual confounding. In addition to being identified as a critical determinant in the decision to initiate dialysis in the surveys, oliguria has been strongly associated with increased mortality in patients with AKI in multiple large observational studies (3,9–11). Interestingly, Wilson et al. did not find an association between urine output and mortality (hazard ratio per 500-ml increase, 1.05; 95% CI, 0.98 to 1.12; P=0.21), which might have been due to the small sample size (5). Independent of urine output, volume overload and diuretic responsiveness may also influence decision making around dialysis. There has been recent interest in the use of fluid overload as a criterion for initiation of dialysis in AKI, based on numerous observational studies that have shown an association between volume overload and mortality (9,12–14). Analysis of a pediatric registry of critically ill patients with AKI reported an 8-fold increased risk of death in patients who were >20% above their premorbid weight at the time of dialysis initiation (14). A similar retrospective analysis of 396 critically ill adults with AKI reported an odds ratio for death of 2.1 (95% CI, 1.3 to 3.4) in those who were >10% volume overloaded (13). These studies are consistent with a recent randomized trial, which supports restrictive volume resuscitation strategies in critically ill patients (15). Finally, the problem of confounding by indication remains difficult to address in observational studies of dialysis initiation regardless of methodology. If dialysis is initiated earlier (at lower serum creatinine levels) in sicker patients who are at a higher risk of death, it is difficult to directly compare dialyzed versus nondialyzed patients. Severity of illness scores such as the Sequential Organ Failure Assessment score used in this study capture some, but not all, aspects of illness, and it remains possible that there were significant unmeasured differences between dialyzed and nondialyzed patients. Despite these limitations, which are common to all observational studies, this study is an important contribution to the ongoing debate about the initiation of dialysis in AKI. The complexity of this analysis demonstrates the difficulty of identifying who will ultimately benefit from treatment. There has been a temporal trend toward earlier initiation of dialysis for the treatment of AKI based on an unproven belief that earlier treatment may result in better outcomes. The results of this study are in direct contradiction to the observational studies supporting early dialysis initiation and suggest that there is sufficient equipoise surrounding this issue to justify a randomized trial of early versus late initiation of RRT in patients with severe AKI. The Standard versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury trial (ClinicalTrials.gov identifier NCT01557361) recently started in Canada. The results of this and similar trials are necessary steps toward answering this question. Disclosures None.

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