In this longitudinal cohort study, at 11 years following PICU admission, 16% of children had evidence of CKD or HTN and 16% had elevated BP or worse. To our knowledge, this is one of the longest AKI vs. non-AKI follow-up studies in a heterogenous PICU population, obtaining patient measures to determine outcomes.
When considering general pediatric population prevalence of CKD and HTN[35, 36], these 11-year outcome rates were very high. We previously identified that low eGFR, albuminuria, and BP abnormalities at 6-year follow-up in this population were high in both AKI and non-AKI children (19%)[24]. Two studies in a general PICU population (including children without AKI) using administrative health data (diagnosis and medication codes)[17, 18] reported 5-year prevalence of CKD and HTN of 1% and 5%, respectively; however, administrative health data have known low sensitivity and these estimates were surely an underestimation of true prevalence. Several studies in the cardiac surgery population have demonstrated persistently elevated 4 to 5-year rates of CKD and HTN, relative to the general population, regardless of AKI status. In a two-center prospective study of children undergoing cardiac surgery, 29% of children without AKI had CKD at 1-year follow-up and 18% had systolic and/or diastolic HTN[37]. Another two-center study of neonates undergoing cardiac surgery found that CKD and HTN were highly prevalent at 6-year follow-up (17% and 30%, respectively); AKI during admission was not associated with CKD or HTN[38]. Cumulative incidence of CKD in children 5 years following cardiac surgery without AKI was 3% in a study using laboratory data from a national registry[39]; and in a study of children following heart transplant, CKD incidence was 5% at 1-year follow-up[40]. These studies support the elevated and persistent kidney risk of critical illness in childhood, irrespective of AKI.
A major knowledge gap hindering development of evidence-based pediatric AKI follow-up guidelines is the lack of prospective, repeated measures describing the natural history of critically ill children with vs. without AKI. In the previously described two-center study following cardiac surgery, CKD and HTN remained prevalent but improved over the 4-year follow-up[37]. CKD or HTN prevalence in our cohort did not worsen from 6 to 11-year follow-up. This may sound like good news; but stated differently, kidney health did not get better. In more detailed analyses, eGFR decreased, but BP improved. This finding begs the question that if by 11-year follow-up, kidney health is not worse, is risk for new CKD or HTN after this time minimal? A study by Robinson et al, using administrative health data from one Canadian province, found that most CKD or HTN diagnoses in children with dialysis-requiring AKI occurred in the first 5 years after discharge[19]. In the pediatric clinical setting, our study and the Robinson study[19] support that the first 5–6 years after illness are a crucial period for ascertaining CKD or HTN. Future research should identify what risk factors or injury biomarkers suggest worse longer-term kidney health prognosis (20–30 years later) in critically ill children with and without CKD or HTN by 5–6 years after AKI.
We previously showed and confirmed herein that AKI during index admission was associated with 6-year follow-up CKD or HTN. AKI was not associated with 11-year composite outcome, but did have an adjusted association with 11-year CKD, low eGFR, and worse BP %iles. Univariable analyses suggested that more severe AKI (stage 2 or worse) was even more strongly associated with 11-year outcomes, suggesting a “dose-response” effect. These findings are consistent with previous studies with shorter follow-up[17, 19, 41–45]. However, our findings also suggest that the impact of AKI may somewhat wane over time; Robinson et al. also found that the impact of AKI on incident CKD and HTN diagnoses lessened with time[19]. Many other factors occur over time which may independently impact CKD or HTN risk. Future research should evaluate the impact of health events over time (e.g., repeat AKI episodes, cardiovascular risk factors like diabetes) on long-term kidney health in hospitalized children.
Our study has limitations. The small sample size reduced power, limiting covariates in the multivariable analyses and possibly effective capture of within-subject variation. However, we believe this study provides a justification to perform larger studies, ideally with a wider spectrum of race and ethnicity, and provides valuable data to help design trials targeting improvement of long-term kidney health. Loss to follow-up potentially introduced selection bias towards sicker children as shown by the higher rate of vasopressor use in participants; however, other illness severity markers were similar. Loss to follow-up was mostly due to inclusion of patients from one of the two original centres and/or geographic distance from centre (despite driving up to 3 hours from centre for study visits). Thus, our findings may not be readily generalizable to rural patients or to those outside of Quebec. The lack of baseline SCr hindered ideal AKI ascertainment; however, this is extremely common in pediatric AKI research[1, 31, 46, 47]. Outcomes were evaluated at a single visit; CKD and HTN should ideally be assessed at multiple visits[28]. However, feasibility and cost of such an endeavour for patients who live far from centre were prohibitive. Instead, we sought to maximize inclusion of patients from the original cohort. Despite the extreme challenges of performing prospective kidney studies in patients who are not routinely followed for kidney health, we also demonstrated that such a study is feasible; families were highly willing to allow us into their homes to obtain relatively invasive measures including bloodwork.
This study provides novel data regarding the evolution of late kidney and cardiovascular outcomes following AKI in critically ill children and progression since our previous 6-year follow-up study. The prevalence of CKD or HTN is significantly elevated, relative to the general population at 11-year follow-up, a high prevalence which persists from 6-year follow-up. The association of AKI with kidney health outcomes likely decreases over time, but future work should confirm that more severe AKI remains most strongly associated with long-term kidney outcomes. Our work supports recent international endeavours to study and recommend pediatric AKI follow-up[23, 48, 49]. Although more research is needed to identify which children with and without AKI are at highest risk for late kidney outcomes, our study strongly suggests that if kidney abnormalities are present at 5–6 years after admission, follow-up must continue. In the context of pediatric care, this will require close collaboration with and education for primary care physicians treating these patients in childhood and adulthood. Considering that post-discharge follow-up of children with AKI is still not systematic, our findings suggest that at the very least, pediatric hospitals should consider evaluating barriers and facilitators to AKI follow-up care in their healthcare context and begin defining key risk groups to target and methods for achieving long-term screening of CKD and HTN.