This study demonstrates that patients who survive AKI have a higher rate of long-term mortality, and other adverse outcomes than patients who survive hospitalization without AKI. The associations were consistent in every clinical setting. With increasing severity of AKI, the association between AKI and death was even stronger, and the association with long-term mortality seemed to be present even in patients with more rapidly reversible AKI. These findings expand upon the results from our previous systematic review that demonstrated the increased risk of short-term death associated with very small changes in serum creatinine.74
Thus, all severities of AKI, even the most mild forms, are associated with both short and long-term survival.
Although we demonstrated a consistent, reproducible association between AKI and long-term adverse outcomes, this does not imply causality. Patients with AKI are often sicker than those without AKI, and AKI is often the complication of multiple organ dysfunction. However, in studies that performed multivariate analyses, the strength of association between AKI and mortality was similar, or greater than that associated with other established risk factors including diabetes, peripheral vascular disease, and chronic obstructive lung disease. Thus, at the very least, AKI can serve as an easily assessable prognostic marker of increased long-term mortality risk.
It remains possible that some of the association between AKI and poor long-term outcomes is causal in nature. As already mentioned, the relationship remained present after controlling for important co-morbidities. In addition, there is biologic support for this relationship as data from experimental animals does demonstrate that AKI can induce tissue injury in other organ systems such as the heart (apoptosis),75
lungs (loss of pulmonary vascular integrity),76
and kidney (fibrosis).11, 12
Despite the reversible nature of clinical AKI where serum creatinine returns to baseline after the episode, AKI may result in permanent injury to other vital organs and thus affect future survival.
If AKI is causally associated with long-term mortality, and not simply a marker for unmeasured risk factors, the most common pathway would be through progression to CKD after an episode of AKI. Although 27 studies examined the cumulative incidence of CKD or ESRD in survivors of AKI, we could not calculate risk ratios for the development of CKD because none of the studies included comparable controls without AKI.
The results of any systematic review are limited by the quality of the primary studies. We assessed the methodologic quality of these studies using accepted criteria. In 41 of the 48 studies, data were collected retrospectively using existing health records. The majority of the studies were single-center studies, thus limiting total achievable sample size and generalizability. Fifteen of the 48 studies did not report whether patients were lost to follow-up, and only 6 of the 15 studies (40%) that followed non-AKI patients adequately adjusted for relevant confounding factors. Nonetheless, the lower bound confidence interval of the risk ratio remained above 1 for all studies that presented adjusted long-term mortality, supporting a consistent relationship. Primary articles used several different definitions for both AKI and CKD, complicating the clinical application of these results. However, the effect was observed across all thresholds of AKI definition, and all-cause mortality is an outcome less prone to bias. It is unfortunate that no studies were able to provide a point estimate for the hazard ratio of CKD or ESRD because of a lack of non-AKI controls. Few studies excluded patients with prior CKD from the reported cumulative incidence of CKD. Also, no studies examined the pattern or slope of GFR decline after AKI over time. This type of analysis would help enlighten the medical community as to whether AKI evolves into CKD abruptly and then plateaus, whether GFR declines in a “step-function”, or whether GFR decreases at a constant rate after an episode of AKI. Many studies also did not have access to a previous “baseline” measure of renal function, prior to the acute illness that would have increased the sensitivity of AKI diagnosis. Most patients were classified as AKI if kidney function deteriorated further after the start of hospitalization, thus representing a more severe phenotype of AKI. Finally, our point estimates should be interpreted with caution, as most pooled estimates invoked a great deal of statistical heterogeneity. We attributed the cause of heterogeneity to the interaction between the definitions of AKI (severity) and clinical setting, as we were able to substantially ameliorate statistical heterogeneity when we accounted for these factors.
While the precise risk for adverse outcomes and death may not be known exactly from our meta-analysis, the consistency of our results suggest that patients who suffer AKI should be monitored closely even after recovery of kidney function for the development of CKD, myocardial infarction, and other potential mediators of poor long-term survival. Future longitudinal studies of AKI should examine larger cohorts of patients (via multi-center prospective studies), with appropriate non-AKI controls, repeated follow-up, and utilize both continuous outcomes (measures of kidney function) and hard-outcomes such as CKD, ESRD, cardiovascular events, and death to truly elucidate the consequences of AKI. Future studies should also rigorously adjust for the level of baseline kidney function when determining the impact of AKI towards CKD. If the suggestion of harm from AKI from this meta-analysis is validated, then determining effective treatment strategies to prevent AKI and adverse outcomes following AKI will be the next challenge that lies ahead for nephrologists and intensivists.