Predictive factors for severe long-term chronic kidney disease after acute kidney injury requiring renal replacement therapy in critically ill patients: an ancillary study of the ELVIS randomized controlled trial

Acute kidney injury (AKI) is a frequent complication in the intensive care unit (ICU) that affects the vital and renal prognosis of patients in the short and long term [1]. ICU patients risk developing chronic kidney disease (CKD) from stage 1 of the KDIGO classification [2, 3]. Several studies have reported an association between increased severity of AKI and an increased risk of developing CKD in the short and long term [2, 4‐7]. The need for RRT is the most severe stage of AKI. Studies report that 70–99% of patients surviving after an AKI requiring an RRT recovered renal autonomy at 6 months and one year [6, 8‐10]. However, long-term renal function in these patients remains unknown. In addition, the modality of RRT used to treat AKI could have an impact on renal recovery depending on whether it is continuous or intermittent [11]. Some studies suggest that renal recovery after AKI is greater when the RRT modality is continuous rather than intermittent [12, 13]. Other risk factors for severe long-term CKD in ICU patients with AKI requiring RRT are unknown [14]. The identification of these factors is a major public health objective. Indeed, early management of these factors could improve the vital and renal prognosis, in particular by reducing the risk of recourse to chronic dialysis, which is a significant burden on public health expenditure [15].

The aim of our study was to identify predictive factors for severe long-term CKD in ICU patients with AKI requiring RRT.

Our study shows that a long RRT period for AKI in the ICU is a risk factor for developing severe long-term CKD. In contrast, a high SOFA score at RRT initiation was associated with a lower risk of developing severe CKD in the long term. These associations are reported here for the first time.

It is now well established that AKI is a risk factor for the development of, or progression to, CKD [1, 3, 5‐7, 14, 19, 20]. Among the features of RRT used in ICU patients with AKI, only the modality of RRT has been suggested as a risk factor for CKD. In a meta-analysis, Schneider et al. showed that among AKI survivors, initial treatment with intermittent RRT can be associated with higher rates of dialysis dependence than with continuous RRT [13]. Sun et al. showed that continuous RRT was associated with the better renal recovery and a shorter RRT period, but without influencing 60-day mortality [21]. These findings are counterbalanced by those of Vinsonneau et al. which showed that there was no difference in mortality (31.5–32.6% p = 0.98) or recovery of renal function (10% vs 7% p = 0.5) between continuous and intermittent RRT [22]. Finally, Truche et al. showed that the modality of RRT did not significantly impact mortality and renal recovery at 6 months [23]. However, this last study suggested mortality was reduced with the continuous modality in the subpopulation of ICU patients with positive fluid balance, and with the intermittent modality in the subpopulation of patients without hemodynamic instability. In our study, there was an association between a long period of RRT during AKI and severe CKD up to 1 year. Because of the small size of the severe CKD group at 3 and 5 years, it was not possible to achieve the statistical power needed to show a significant difference after 1 year. Few studies have assessed the impact of AKI duration in the ICU on long-term renal function. Mehta et al. showed in a meta-analysis that a long duration of AKI was a risk of developing CKD [24]. To our knowledge, our study is the first to show that a long period of RRT is associated with a higher risk of severe CKD in the long term. There are several possible explanations for this observation. It may be that the period of AKI during which RRT is required, is associated with the severity of renal lesions. Several studies have shown that the severity of an AKI is a risk factor for developing CKD [4, 5]. In addition, it has been shown that RRT exposes patients to per-procedure arterial hypotension, which is sometimes undetected and could cause ischemic kidney damage [25]. Such ischemic lesions can contribute to the delay of renal recovery, which would promote the fibrotic cellular processes leading to CKD [26]. It seems that RRT is both the consequence of the severity and a factor in the prolongation of the renal lesional process and thereby prevents optimal renal recovery. Many other factors such as hypertension, diabetes, and older age are involved in the development and progression of CKD [3]. Some of our included patients had risk factors that have contributed to the development of severe CKD.

Our study showed an intuitively surprising association between a high SOFA score [27] and the development of long-term low-severity CKD. This association persisted throughout the duration of the follow-up, i.e., 5 years after the AKI. There is no pathophysiological relationship to explain this finding. It could be due to a selection bias in the study population. Patients who had a high organ failure score either died (most often within 3 months) and therefore were not included in the study, or survived without renal sequelae. The two findings of our study suggest that ICU patients who had an RRT period of less than 20 days and who survived despite a significant number of organ failures, had a good renal recovery in the long term. The AKI could mainly result from other organ failures. In survivors, the recovery of these failures leads to a renal recovery. Otherwise, the comorbidities “chronic hypertension” and “insulin-dependent diabetes” were not associated with the severe CKD group, while these comorbidities are well-established risk factors for CKD. Only 13% of patients suffered from insulin-dependent diabetes and 41% suffered from chronic hypertension, so our study might be underpowered to show a difference in the impact of these comorbidities between the two CKD groups. Our results should be taken into consideration in future studies on the prognosis of ICU patients treated with RRT. It is possible that in addition to the modality of RRT, its duration could have an impact on long-term renal recovery and therefore on patient prognosis.

Our study has several limitations. First, the duration of the RRT period depends on when it was initiated and on the weaning criteria. There is currently no international consensus regarding the criteria for the initiation and weaning of RRT, and hence our findings were not affected by a modification of these criteria. The ELVIS trial [16] was carried out before several randomized controlled trials that suggested delaying the initiation of RRT since 40 to 50% of patients who have severe AKI achieve rapid renal recovery, which avoids RRT with no impact on mortality [28, 29]. However, we do not believe that the new suggested criteria for the initiation of RRT would change our results because the duration of RRT in these trials was very short, from 2 to 4 days, which suggests that AKI was less severe than in our study probably owing to a different case mix. However, almost all of the patients included in our study had a 4-point renal SOFA criterion, which corresponds to less than 200 ml/24 h of diuresis or serum creatinine > 440 µmol/L, whereas mean serum creatinine level in the trial participants at the initiation of RRT was less than 300 µmol/L [28‐30]. It is therefore unlikely that our study included patients who could have avoided RRT. Similarly, the impact of modifying RRT methods is unlikely, given the absence of any major publications leading to new recommendations for changing practices. Second, the design of our study did not make it possible to ensure that all creatinine levels were measured at each timepoint. Twenty-two patients had a serum creatinine value available between 3 months and 5 years and were alive at 5 years. However, our choice of missing data imputation did not adversely affect the risk of severe CKD because the imputed CKD stage was equal to the more severe of the two stages before or after the timepoint for which data were missing. Thus, our imputation methodology could have identified severe CKD before it actually occurred. Some elderly patients improved their renal function between 3 and 6 months or even up to 1 year and hence changed CKD stage accordingly. We assume that the renal function of the elderly patients took several months to be fully recovered because of the structural and functional changes associated with the aging kidney [31]. Moreover, the baseline of serum creatinine level before ICU admission was not collected in the ELVIS database. Only the variable eGFR ≤ 60 ml/min/1.73 m² was collected, which may have been estimated with means other than CPK-EPI, and this could explain why some of these patients were in the no/mild group. We assessed the occurrence of CKD after AKI requiring RRT and not the renal recovery of patients. Third, generalizing our findings to all critically ill patients requiring RRT for AKI should be cautious because of the lack of information on a significant number of patients who were lost of follow-up or did not have bloodwork at the different timepoints assessed in the study.

Severe long-term CKD is found in one-fifth of ICU survivors treated with RRT for AKI. The duration of the RRT period has been identified as a risk factor for developing severe CKD in the long term. Our findings should be considered in future studies on the prognosis of ICU patients treated with RRT.