Introduction

Acute kidney injury (AKI) occurs in approximately 10–15% of hospitalized patients; however, its incidence in the intensive care unit can be more than 50% of patients1. Previous meta-analyses and systematic reviews have demonstrated that AKI might significantly increase the risk and progression of chronic kidney disease (CKD) as well as the risk of end-stage kidney disease (ESKD) and even mortality2,3,4,5,6. However, a recent prospective study determined that AKI stages were not independently associated with adverse clinical outcomes after adjustment for multiple CKD risk factors7.

Acute kidney disease (AKD), as an intermediary stage between AKI (abrupt deterioration of renal function within a period of 7 days or less) and CKD (persistent renal function impairment or structural abnormalities for more than 90 days), indicates changing renal function that could be strongly associated with long-term renal outcomes and could serve as a valuable indicator of the appropriate time window for therapeutic interventions2,8,9. A large population-based observational study discovered a statistically significant association between AKD and major adverse kidney events (MAKEs) related to CKD progression, ESKD, and mortality10. With or without AKI, AKD was also found to be associated with adverse clinical outcome among hospitalized patients11.

Nevertheless, the disparate definitions of AKD might indicate variance in the acuity and severity of kidney disease among different subgroups of AKD patients12. Persistent kidney dysfunction for more than 7 days after AKI (post-AKI AKD) is associated with adverse renal and cardiovascular outcomes11,13,14,15,2, recommending a clinical classification based on SCr data. The criteria of post-AKI AKD stages are congruent with the KDIGO guidelines on AKI stages. Chen et al. studied a cohort of patients on extracorporeal membrane oxygenation and observed that AKD stages were independent risk factors for mortality22. In the present study, we further delineated the prognostic effects of different AKD stages related to various MAKEs. Regarding MAKEs at 1 year, a more severe AKD stage was noted to be associated with worse kidney outcomes. Moreover, the risk of 1-year MAKEs seemed to increase in direct proportion with AKD stage. AKD was also associated with an increased risk of in-hospital mortality, both in the lower baseline eGFR and the higher baseline eGFR groups.

Compared with the AKD stage 0 group (SCr returning to lower than 1.5-fold of baseline value between 7 and 90 days after AKI), the group with all other AKD stages (AKD stages 1, 2, and 3) had a higher probability of eGFR decline of more than 35% beyond 90 days after AKI. Moreover, non-recovery of kidney dysfunction within 7–90 days after AKI reasonably predicted persistent kidney damage beyond 90 days after AKI and the development or deterioration of CKD. Heung et al. conducted a retrospective study using a large administrative database of the veterans’ health system, in which also found that the persistently elevated SCr after AKI was associated with the development of CKD within 1 year, regardless of AKI severity23.

Regarding KRT initiation, only patients with AKD stages 2 and 3 had a higher risk of requiring KRT. It was also noted that only AKD stage 3 was associated with prolonged dialysis. This finding precisely indicates that the AKD stages should be congruent with AKI stages, with one of the criteria of stage 3 AKI being “dialysis-requiring AKI (AKI-D)”. The present study confirms that stage 3 AKD is likely to progress to “dialysis-requiring AKD (AKD-D)”. Therefore, patients with AKD with either “SCr increased to more than 3 times of the baseline SCr” or “unresolved dependency on dialysis” should be categorized as having stage 3 AKD (AKD-3).

There are several limitations in our study. First, in our algorithm for the definition of acute kidney injury (AKI) (Fig. S1), we adopted NHS England AKI algorithm and used two strategies to define baseline SCr. We first searched for the lowest SCr within 0–7 days before the index SCr as baseline. If such an baseline SCr were not available, we then searched median value of all available SCr data within 8–365 days of the index as reference SCr. Different definitions of baseline SCr may result into higher or lower rate of AKI diagnosis24. However, previous studies have validated the robustness of such algorithm25,26. The AKI events defined by the NHS England AKI algorithm could also be used as gold-standard in the machine learning prediction study27. Second, we retrieved the maximum SCr value between 7 and 90th day after AKI for AKD staging. Within this post-AKI time period, AKI recovery and multiple AKI episodes might occur. Also, dialysis might affect the SCr value during post-AKI period. However, whether recurrent AKI or a very high pre-dialysis SCr may be all considered as “non-recovery” during the post-AKI period. Severe AKD (AKD stage 1–3) by SCr still represents the persistence or the aggravation of kidney dysfunction following AKI. Third, many patients with AKI had no SCr data between 7 and 90 days after AKI for defining and staging AKD. The proportion of missing data within this period was markedly high, at approximately 43% (3781 patients out of 8718 patients). The lack of follow-up SCr data might be attributed to early mortality, early recovery from AKI, and most likely unawareness of the occurrence and significance of AKI. A recent analysis by Wu et al. in Taiwan revealed that only 37% of patients with dialysis-requiring AKI (AKI-D) weaned from dialysis received the nephrologist follow-up during the AKD period28. AKI electronic alert (AKI eAlert) systems29,30,31, might increase the awareness of AKI and facilitate follow-up SCr data generation and help reduce the hospital stay duration when it is coupled with care bundle32.

Proteinuria has been noted to be an independent risk factor for predicting the development and severity of AKI among surgical and hospitalized patients33,34,35,36,37. Recently, Hsu et al. demonstrated the significance of post-AKI proteinuria in a multicenter, prospective cohort study of patients with AKI, wherein a higher post-AKI urinary albumin-to-creatinine ratio (ACR) was noted to be associated with rapid kidney disease progression7. Notably, after adjustment for the ACR and traditional clinical kidney disease risk factors, AKI stages were not observed to be independently associated with adverse clinical outcomes. In our longitudinal follow-up study, baseline proteinuria data were available for only approximately 18% of patients with AKI. Therefore, proteinuria level cannot be used either as a baseline characteristic to define CKD status or clinical predictor for renal disease progression. Regarding the severity of kidney disease, namely the stages of post-AKI AKD, the present study observed a significant association between different AKD stages and various adverse clinical outcomes. Furthermore, more severe AKD stages were noted to be associated with higher risks of in-hospital mortality, renal disease progression, and need for dialysis.

Second, local regulations do not permit the linkage of our single-hospital database with the National Health Insurance Research Database (NHIRD). Therefore, certain adverse clinical events might have occurred at another hospital without being documented in our health information system.

In conclusion, after AKI, we found that AKD stage 1–3 were common among AKI patients. Post-AKI AKD is associated with an increased risk of eGFR decline, need for KRT, and in-hospital mortality among patients with lower and higher baseline eGFR. Moreover, AKD is associated with a higher risk of requiring prolonged dialysis among patients with baseline eGFR < 60 mL/min/1.73 m2. Therefore, timely intervention with intensified care program shall be established and embed into the health care system to stop the AKI-AKD-CKD continuum.