Background
Acute kidney injury (AKI) is a common and serious complication of hospitalization; in severe cases, urgent renal replacement therapy (hereafter referred to as dialysis) is needed to address complications of AKI and to support the patient in overcoming the acute illness. Between 2000 and 2009, the incidence of dialysis requiring AKI (AKI-D) in the United States increased by 10% annually from 222 to 533 cases per million person-years [
1]. The increased incidence of AKI will result in greater numbers of patients who are faced with persistent health challenges after the acute phase of their illness has resolved. As a result, acquisition of a better understanding of AKI survivors, who are at increased risk of progressive kidney disease, and death, is of vital public health importance [
2‐
5].
Recognition that survivors of AKI are at high risk of progressive chronic kidney disease (CKD) spurred the Kidney Disease Improving Global Outcomes (KDIGO) AKI guidelines to recommended that kidney function should be evaluated 3 months after an AKI episode to establish the presence and extent of chronic kidney disease [
6] However, others have advocated that Nephrology follow-up occur for all patients with severe AKI [
7]. With almost 1 in 5 adults worldwide experiencing an episode of AKI during a hospitalization, two percent of whom require dialysis, such a broad referral strategy may be impractical [
8]. Identifying AKI-D survivors at the greatest risk of progressive CKD would potentially lead to the targeted follow-up for individuals who are most likely to realize a benefit. Accordingly, in a cohort of AKI-D survivors, we performed a study to determine the predictors of permanent maintenance dialysis and secondarily, death.
Discussion
Escalating comorbidity, pre-existing kidney disease, as reflected by a diagnosis of CKD or a visit to a nephrologist, and pre-existing hypertension predicted progression to chronic dialysis in a cohort of patients who survived an episode of dialysis-requiring AKI. Similarly, increasing age, a higher Charlson comorbidity score; the presence of heart failure, diabetes and dementia were predictive of post-AKI mortality.
Although the link between AKI and subsequent CKD has been extensively described, patients with the most severe form of AKI who require acute dialysis are the sub-population of patients with the highest risk of progression [
16]. However, we found that only 10% of these patients progress to chronic dialysis thus highlighting the need to identify risk factors for such progression in order to target potential interventions to those who are most likely to benefit. Moreover, due to our study design, patients with severe AKI who did not recover renal function or those who initiated chronic dialysis within 90 days of discharge were excluded from our cohort; and therefore, the contribution of AKI to the progression to chronic dialysis is likely higher than our data suggests.
Similar to our report, studies by Stads et al. [
17], Ishani et al. [
18], and Lo et al. [
3] have demonstrated the strong association between pre-existing CKD and the need for subsequent chronic dialysis. It is not surprising that pre-existing CKD is one of the most important predictors modifying the relationship between AKI and progressive CKD as has been demonstrated in multiple studies [
19‐
22]. The impact of even a modest acute insult to already compromised kidneys may be devastating. Although the biological mechanism linking CKD progression after AKI has not fully been elucidated, it has been postulated that the combination of acute endothelial injury leading to vascular dropout, and nephron loss followed by glomerular hypertrophy and the development of fibrosis may all play a role [
23,
24]. This may be more pronounced in patients with underlying CKD who may already possess a limited renal reserve, such that an episode of AKI may tip them into the need for chronic dialysis more easily than those without a background history of renal disease. Recognizing the limited performance of CKD diagnosis codes, we enhanced our capture of patients with underlying kidney disease by examining prior visits to a nephrologist, which we postulated as a reasonable surrogate for kidney disease. Both prior visits to a nephrologist and/or diagnosed CKD together capture the notion that patients who develop severe AKI with already-compromised kidney function are at substantially higher of accelerated and irreversible kidney dysfunction once the acute illness resolves.
As demonstrated by Chawla et al., we found that hypertension was another important predictor of chronic dialysis among AKI-D survivors [
25]. Systemic hypertension is a potent contributor to the development of arteriosclerosis, tubulointerstitial fibrosis and glomerulosclerosis, all of which may hasten the decline in kidney function [
26,
27]. Patients with a history of hypertension may have underlying unrecognized CKD, despite having a “normal” serum creatinine level [
28,
29]. Subsequent renal injury imparted by an episode of AKI may not only unmask this underlying damage, but also lead to its acceleration.
The inverse association between liver disease and chronic dialysis was surprising given that these patients are prone to ongoing renal injury from changes in autoregulation due to arteriolar vasodilation and neuroendocrine changes associated with decompensated liver disease [
30]. Perhaps, this group of patients underwent acute dialysis during their hospitalization as a bridge toward subsequent liver transplantation. Indeed, serum creatinine is a component of the Model for End-Stage Liver Disease (MELD) score which is used for organ allocation in patients with liver disease [
31]. Severe AKI associated with liver disease is associated with extremely high mortality [
32]. We speculate that the few individuals with liver disease who survived a hospitalization associated with AKI-D had a relatively lower burden of comorbidity. By the same token, the apparent “protective” association between mechanical ventilation on the index hospitalization and both chronic dialysis and all-cause mortality suggests that the sickest patients who received mechanical ventilation likely died during the hospitalization or shortly thereafter. Those fortunate to survive to 90 days following discharge were a selected group who by virtue of surviving the acute phase of their illness, were destined to have better outcomes.
Since the risk of death after an episode of AKI-D far outstrips that of chronic dialysis, predicting this outcome is also of vital clinical interest. As such, our study also delineated a number of predictors of post-AKI mortality including increasing age, a higher Charlson comorbidity score; the presence of heart failure, diabetes and dementia; as well as an inverse relationship with the receipt of mechanical ventilation. In line with previous work by Stads et al., preexisting CKD was strongly associated with death, which may relate to the link between CKD and cardiovascular disease [
17,
33].
Our study has several strengths. Most notably, it is the first to determine the predictors of initiating chronic dialysis in a cohort of survivors of severe AKI using a competing risk approach. Although previous studies of AKI survivors have reported similar predictors, there are notable differences in methodology, case-mix and outcome ascertainment between these studies and ours [
3,
5,
18,
25,
34]. Our use of a competing risk approach, may have avoided overestimating the cumulative incidence of the progression to chronic dialysis in survivors of severe AKI [
35], and also gave us more robust effect estimates for our predictors [
35]. Finally, our study was conducted in a jurisdiction with universal access to medical services and our databases reflect the entire population, maximizing generalizability. Though non-dialysis requiring CKD following AKI - is common and potentially problematic, we focused our attention on the extreme form of CKD, chronic dialysis, which has the most profound implications for quality of life and survival [
2].
Our results have several potential implications. First, the identification of novel predictors of chronic dialysis in survivors of severe AKI may help improve the follow-up of these patients by selectively referring to nephrologists those patients who possess characteristics which place them at a high risk of progression. There is compelling data regarding the positive role that nephrologists may play in survivors of severe AKI; however, only a small proportion of severe AKI survivors are referred to a nephrologist for follow-up [
2,
11]. This may be related to limited access to nephrologists or an under-appreciation of the risk for progressive CKD following AKI. Alternatively, a select number of patients with pre-existing chronic kidney disease may already be followed by a nephrologist prior to their episode of AKI, and this continuity in care persists after the episode; thereby, obviating the requirement of a new referral. Second, knowledge of predictors of chronic dialysis may allow for the creation of a predictive model that can stratify AKI survivors at highest risk for progression to CKD for inclusion in clinical trials.
Several limitations merit consideration. First, our reliance on administrative codes for diagnoses and procedures limited our ability to better characterize the cohort and incorporate potentially vital data (eg, severity of acute illness, laboratory data) in to our models. In particular, the absence of pre-hospitalization laboratory data, most notable serum creatinine to estimate the glomerular filtration rate and information on proteinuria, is an important limitation [
22,
25]. As an alternative, we could only describe CKD using administrative coding, which is highly specific but poorly sensitive (median sensitivity 41%; median specificity 98%) [
36], and by the surrogate of prior visits with a nephrologist which is an important shortcoming. Moreover, the administrative databases that we used did not contain data (laboratory and clinical data), which would have allowed us to determine illness severity (e.g., SOFA and APACHE scores). As these scores are useful predictors of outcome failure to account for them in our propensity score may have also contributed to confounding. Our inability to access preadmission laboratory data also precluded us from conducting more rigorous analyses with more robust measures of chronic kidney disease. Similarly, we had no way of evaluating the extent of kidney function recovery at the conclusion of the acute illness. Compromised residual kidney function following an episode of acute kidney injury is likely an important predictor of progression to chronic dialysis. Our definition for the receipt of chronic dialysis may have misclassified individuals who truly developed end-stage renal disease, but who died in the first 90 days after commencing chronic dialysis. However, our definition for the receipt of chronic dialysis is widely accepted, and has been used in multiple studies [
5,
11]. In addition, while it is interesting that greater global comorbidity, as expressed via the Charlson score, was associated with chronic dialysis and death, we could not identify which aspect(s) of the multicomponent Charlson score was most important. Ultimately, our predictive models showed limited discriminatory capacity suggesting that several factors that our datasets could not capture could have been relevant in anticipating important clinical outcomes following an episode of AKI. Moreover, we only examined a cohort of individuals who experienced the most severe form of AKI. In this regard, our findings may not be generalizable to individuals experiencing less severe yet much more common forms of AKI.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
ZH, and RW were involved in the study concept, design and coordination, data analysis, and helped to draft the manuscript. SH, AXG, MTJ, CMB, SND, EM, and SS were involved in the analysis of the data, and helped to draft the manuscript. All authors read and approved the final manuscript.