Severe Acute Kidney Disease Is Associated With Worse Kidney Outcome Among Acute Kidney Injury Patients Ⅳ

Discussion 

In our longitudinal follow-up study involving 4741 AKI patients, all the patients were considered as having AKD by the current KDIGO consensus15. In both the lower baseline eGFR group and the higher baseline eGFR group, more than 50% of the patients had stage 1–3 AKD. The dauntingly high incidence of severe AKD matches with previous studies. In a multicenter retrospective cohort study conducted by Xiao et al., 53.17% (1359/2556) of the AKI patients developed AKD16. In a single center 10-year follow-up study by Nagata et al., AKD patients accounted for 66.8% of all AKI patients14. Although a definition of AKD was proposed in the KDIGO AKI guidelines in 2012, limited data have been published regarding the clinical significance of AKD7,10,21. The KDIGO definition of AKD comprises the following criteria with the same timeline of fewer than 3 months: (1) AKI (congruent with AKI), or (2) GFR<60 mL/ min/1.73 m2 (approximating CKD), or (3) decrease in GFR by> 35%, or increase in SCr by> 50% (rapid progression of renal dysfunction between AKI and CKD)12,15. James et al. separated patients with post-AKI AKD and patients with AKD without AKI. After a 10-year follow-up of a 1-year regional cohort, they successfully demonstrated the clinical significance of AKD without AKI. Notably, compared with patients without kidney disease, those with AKD without AKI had higher risks of mortality, ESKD, and development or progression of CKD10. However, this study involving a retrospective cohort did not address the severity of AKI and post-AKI AKD, and thus, it could not provide information regarding the risk stratification among AKI patients. In a recent comparative analysis by See et al., among all the 36,118 hospitalized adults with a baseline eGFR≥60 mL/ min/1.73 m2, AKI, AKD with AKI, and AKD without AKI were all associated with worse kidney outcomes and higher mortality risk11. Interestingly, in keeping with our findings, multivariable Cox regression analysis of the risk of MAKEs found that the hazard ratios for MAKE of AKI alone group and AKD with AKI (post-AKI AKD) group were widely separated, which may represent significantly different risks between the two groups [AKI alone, HR 1.52 (95% CI 1.35–1.72) VS AKD with AKI, HR 2.51 (95% CI 2.16–2.91)]. In the present study, we further proved that post-AKI AKD was associated with worse clinical outcomes, not only in hospitalized adults with a baseline eGFR≥60 mL/min/1.73 m2 but also in those with baseline eGFR<60 mL/min/1.73 m2 (lower baseline eGFR group) across all clinical settings (all EMR data in our analysis comprised data from hospitalized patients and outpatient clinic patients). Different stages of post-AKI AKD have diverse clinical outcomes. Notably, international experts have achieved a consensus regarding AKD staging2, 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 to the 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.

A NEW HERB FOR CURING KIDNEY DISEASE

Figure 3. Adjusted odds of major adverse kidney event at 1-year follow-up in lower baseline eGFR group. Odds of major adverse kidney events stratified by the most severe stage of AKD between 7–90 days after, according to 16th Acute Disease Quality Initiative (ADQI) recommendations, in the lower baseline eGFR group. Adjusted odds ratios (dots) and 95% CIs (lines) were calculated using logistic regression, where the reference category was patients who were AKD stage 0. Logistic regression was adjusted for age, sex, hypertension, heart disease, diabetes, anemia, cerebrovascular disease, cancer, COPD, and digestive tract disease. Clinical significance was observed while comparing AKD stages 1–3 versus stage 0. AKD acute kidney disease, AKI acute kidney injury, eGFR estimated glomerular filtration rate, COPD chronic obstructive pulmonary disease.

A NEW HERB FOR CURE KIDNEY DISEASE

according to 16th Acute Disease Quality Initiative (ADQI) recommendations, in the higher baseline eGFR group. Adjusted odds ratios (dots) and 95% CIs (lines) were calculated using logistic regression, where the reference category was patients who were AKD stage 0. Logistic regression was adjusted for age, sex, hypertension, heart disease, diabetes, anemia, cerebrovascular disease, cancer, COPD, and digestive tract disease. Clinical significance was observed while comparing AKD stages 1–3 versus stage 0. AKD acute kidney disease, AKI acute kidney injury, eGFR estimated glomerular filtration rate, COPD chronic obstructive pulmonary disease.

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, 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 the NHS England AKI algorithm and used two strategies to define baseline SCr. We frst searched for the lowest SCr within 0–7 days before the index SCr as baseline. If such a baseline SCr were not available, we then searched the median value of all available SCr data within 8–365 days of the index as reference SCr. Different definitions of baseline SCr may result in a higher or lower rate of AKI diagnosis24. However, previous studies have validated the robustness of such an 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 days after AKI for AKD staging. Within this post-AKI period, AKI recovery and multiple AKI episodes might occur. Also, dialysis might affect the SCr value during the 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) systems29–31, might increase the awareness of AKI 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 patients 33–37. 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, proteinria 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 signifcant 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 stages 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 an intensifed care program shall be established and embedded into the health care system to stop the AKI-AKD-CKD continuum.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author. 

Received: 5 October 2021; Accepted: 9 March 2022