Associations between physical activity levels and renal recovery following acute kidney injury stage 3: a feasibility study

Patients with acute kidney injury (AKI) experience both short- and long-term adverse health outcomes [1]. The immediate complications such as electrolyte, fluid and acid–base disturbances, are well recognised and have established management strategies [2]. In contrast, the long-term effects of AKI that are conferred through the development of chronic kidney disease (CKD), such as increased risk of cardiovascular disease, mortality and progression to end-stage kidney disease (ESKD) are not addressed to the same extent [1]. It was previously thought that kidney damage completely resolves after AKI, however it is now understood that there is often sustained renal dysfunction [3]. Despite this, there are currently no targeted treatments aimed at improving post-AKI renal function. Many novel therapeutic interventions such as alpha melanocyte stimulated hormone, low dose furosemide and alkaline phosphatase have been trialled [4‐6] with limited success, emphasising the requirement for new treatment strategies.

Data from animal models [7‐13] demonstrate that increased levels of physical activity may be protective and promote renal recovery following an episode of chemically-induced AKI. The proposed mechanism includes the anti-inflammatory effects of increased activity [9, 10] attenuating renal damage through controlling low-grade chronic inflammation that may sustain renal damage. A reduction in fibrotic [8] and oxidative pathways, [8, 10, 11, 13] and autophagy upregulation [7, 11] improve cell survival and kidney function in physically active animals post AKI. These data suggest a possible role of exercise in attenuating renal damage post AKI, thereby improving patient outcomes.

Despite these promising animal models, at present there is a paucity of data on the association between exercise and physical activity levels and AKI recovery in humans. More specifically, since an increase in AKI severity is associated with an increased risk of CKD and ESKD [14], AKI stage 3 individuals would benefit the most from an improvement in their renal function post AKI. Additionally, as patients with AKI are usually acutely unwell and no previous study has tried to enrol these participants into a physical activity study, the feasibility of conducting such a study in this patient group is unclear.

Therefore, the aims of this observational study are to: explore the associations between physical activity levels and renal recovery following an episode of AKI stage 3 and; evaluate the feasibility of a study of physical activity in the AKI population.

This is the first study to measure physical activity in individuals following an episode of stage 3 AKI. We observed an association between higher levels of physical activity and improved renal function. Individuals with higher physical activity levels, assessed via the GPPAQ questionnaire, had consistently lower creatinine levels at 1- and 6-months post discharge. This association is in keeping with data from the 6-month step count as those with a higher average daily step count had greater renal recovery at 6 months post-discharge. We also observed an association between higher levels of physical activity prior to AKI and better recovery in the post AKI period. We observed in patients with AKI stage 3 that renal impairment persisted at discharge with maximum renal recovery being achieved 3 months post discharge, as no further recovery was noted at 6 months. Lastly, we measured the feasibility of a study observing physical activity levels in individuals following an episode of AKI. We screened a large number of individuals with only few meeting the eligibility criteria and being subsequently enrolled to participate. Additionally, many participants were lost to follow up at 3 and 6 months.

Numerous pre-clinical animal studies show that increasing physical activity attenuates renal damage post-AKI, highlighting the fact that there is biologically plausibility behind our findings. The transferability of these animal findings in the human setting has been questioned [25, 26]; however our results support the association between improved renal recovery in more physically active individuals [27]. Physical activity in the AKI population has not previously been reported. Furthermore, we found no studies which correlate physical activity with renal recovery in the AKI setting. However, the pattern of renal recovery observed in our study, whereby recovery continued post discharge, is well established [28]. Furthermore, it is known that those with recovery following AKI have better outcomes than those with persistent renal impairment. In addition, time to recovery is a valuable clinical parameter as those with longer recovery times have worse long-term outcomes such as a higher incidence of CKD, long term dialysis use and increase in mortality [29]. This study observed that the greatest amount of renal recovery occurred in the 3 months post-discharge, therefore any future interventions aimed at recovering renal function would be most beneficial if implemented during this time frame.

The association observed between increased levels of physical activity and improved renal recovery does not imply causation. It is possible that individuals may have been more active because of improved renal recovery. Furthermore, those who were more active prior to AKI may have had better overall health hence facilitating their faster recovery in renal function. This is supported by studies [30, 31] that report associations between poor pre-operative cardiorespiratory functioning and worse post-operative outcomes, such as longer stay in intensive care and increased short- and long-term morbidity and mortality. Additionally, randomised controlled trial (RCT) data has demonstrated that pre-operative exercise training decreases post-operative complications in patients undergoing elective abdominal aortic aneurysm repair [32] and coronary artery bypass graft surgery [33], indicating that healthier individuals prior to hospitalisation have better outcomes. It is therefore not clear whether our observations showing associations between improved recovery and renal function post AKI have implications for long-term outcomes in this population. Furthermore, it is unclear whether increasing physical activity levels (through a targeted intervention) following AKI, would lead to an improvement in renal recovery. Regardless, since our study demonstrates an association between increased levels of physical activity and improved renal function, this warrants further investigation.

In this study only a small number of the screened patients fulfilled our inclusion criteria. The three most common reasons for ineligibility were: underlying severe CKD, obstructive uropathy and patients achieving full renal recovery prior to discharge. A wider inclusion criteria should be considered for future studies. This can be achieved by including individuals with stage 1 and stage 2 AKI. More specifically, those with an increased risk of CKD progression following AKI should be identified and recruited. Whilst increase AKI severity is a risk factor for CKD progression, other factors such as the number of AKI insults and presence of other CKD risk factors such as diabetes mellitus and hypertension are also important to consider [34].

Out of those who were approached, the majority (59%) consented to participate. We found large losses to follow up at both 3- and 6-months post discharge. Only a small amount of these were attributed to participant death and withdrawal of consent from the study. Based on prior research, it is possible that difficulties in participant retention may be explained by our cohort belonging to an older age demographic, 68 (± 17) years. Difficulties in both recruitment and retention in > 65 years have been previously demonstrated [35]. Decline in overall health, loss of interest, failure to recognise research benefit and increase frailty have previously been reported as reasons for lack of retention in research studies in this age group [35, 36]. It is plausible that our study could also have been impacted by these factors. Different strategies have been proposed on how to combat these issues. Many of which were already part of our study design, most notably the remote nature of our data collection process whereby individuals were able to complete the follow up questionnaires at home. Methods to increase retention in future studies include regular follow up phone calls to keep participants engaged in the study. Widening the inclusion criteria to the possible addition of stage 1 and stage 2 AKI individuals would also create a more age-diverse cohort hence addressing the issues seen mostly in > 65 year demographic. With the successful addition of strategies to reduce loss of follow up, our data supports that larger scale studies of physical activity would be feasible in the AKI population.

These data demonstrate that a RCT designed to investigate the effect of exercise on renal recovery post AKI is feasible. At present, there are still no effective interventions that improve renal recovery and thus reduces the long term sequalae of an episode of AKI [37]. This feasibility study provides hypothesis generating data, however due to the limitations of our sample size, the results must be interpreted with caution. A future, large scale RCT is needed to definitively test the hypothesis that a programme of exercise may have a positive impact upon renal recovery.

This feasibility study demonstrates a possible association between higher levels of physical activity and improved renal recovery after 3-months following an episode of stage 3 AKI. A future randomised controlled trial is feasible and would be required to confirm these initial findings.