Invited Commentary <\/p>\n\n\n\n
Nephrology<\/p>\n\n\n\n
March 8, 2024<\/p>\n\n\n\n
Acute kidney injury (AKI), acute kidney disease (AKD), and chronic kidney disease (CKD) have been defined as discrete entities but in practice can form a continuum whereby an initial kidney insult can lead to persistent damage, resulting in chronic fibrosis, CKD, and end-stage kidney disease (ESKD). This study by Pan and colleagues1<\/a><\/sup>\u00a0analyzed a statewide population-based database and found that patients admitted to an intensive care unit (ICU) in Chinese Taipei who survived an episode of dialysis-dependent AKI (AKI-D) had a particularly high risk of dying or experiencing an incident major adverse cardiovascular event (MACE) in the short and long term. Of 6703 patients included in the analysis, 37% died during hospitalization and 12% died within 90 days after discharge. The risk of continuing or resuming dialysis within this 90-day period was alarmingly high, affecting more than half of the surviving patients. Among patients who discontinued dialysis and were alive 90 days after discharge, 28% died, 17% developed ESKD, and 11% developed an incident MACE within 1.2 years of follow-up. Kidney function at baseline and kidney function after AKD (measured 90-135 days after discharge) were independently associated with all-cause mortality, ESKD, MACE, and hospital readmission. Interestingly, the severity of AKD (defined by relative increases in serum creatinine compared with the lowest value 7-90 days after discharge) was not associated with long-term risks.1<\/a><\/sup>\u00a0The association of post-AKD kidney function corresponding to CKD categories 3 to 5 with risk of death remained consistent across subgroups based on age, sex, comorbidities, and use of renin-angiotensin-aldosterone system inhibitors (RAAS-I). A surprising finding was that patients with AKI-D and preexisting CKD categories 3 to 5 had significantly lower long-term mortality but worse kidney outcomes than patients with baseline estimated glomerular filtration rate greater than 60 mL\/min\/1.73 m2<\/sup>.1<\/a><\/sup><\/p>\n\n\n\n These important findings underscore the critical impact of AKI-D on patient outcomes, both during and after a hospital stay. It should be acknowledged that Pan et al1<\/a><\/sup> restricted the cohort to ICU patients who had AKI-D, recovered kidney function, were alive at day 90 after discharge, and had blood results available from prior to ICU admission and between 90 and 135 days after discharge to determine baseline and follow-up kidney function. Furthermore, the 90-day period used to diagnose AKD accrued from the date of discharge rather than onset of AKI, as it has been framed elsewhere.2<\/a><\/sup> Nevertheless, the results of the study by Pan et al1<\/a><\/sup> highlight the interconnectedness of AKI-D, preexisting and subsequent CKD, ESKD, and cardiovascular disease. Despite a better understanding of these interrelationships, important questions remain:<\/a><\/p>\n\n\n\n The mechanisms linking AKI and cardiovascular events may be bidirectional, whereby new cardiovascular events develop in survivors of AKI or, alternatively, underlying preexisting cardiovascular risk factors underlie the development of AKI. For instance, a study in 43\u202f611 hospitalized patients found that AKI was independently associated with 22% increased odds of developing hypertension.3<\/a><\/sup> Alternatively, patients may have had undiagnosed hypertension as a risk factor for AKI.<\/a><\/p>\n\n\n\n The association between AKI and increased mortality is similarly complex, and relatively little is known about causes of death. A population-based study from Canada reported that 28% of patients who survived hospitalization with AKI died in the year after discharge, and the most common causes of death were cardiovascular disease (28%) and cancer (28%), according to death certificates.4<\/a><\/sup><\/a><\/p>\n\n\n\n While kidney and cardiovascular outcomes are primary concerns, adverse outcomes extend beyond these systems. For instance, sepsis is not only a common cause of AKI but also a frequent complication after AKI, particularly among patients with AKI-D. The mechanisms underlying this increased susceptibility and the effectiveness of potential preventive strategies are currently unknown.<\/a><\/p>\n\n\n\n Survivors of AKI have also been reported to have an increased risk of cerebrovascular disease, diabetes, new onset atrial fibrillation, cancer, and fractures.5<\/a><\/sup> These adverse outcomes may be directly related to AKI or the result of changes in medications, like RAAS-I, immunosuppressants, or chemotherapy. The impact of AKI-D on health-related quality of life is unclear and confounded by comorbidities and the lingering after-effects of critical illness, including frailty and financial difficulties.6<\/a><\/sup><\/a><\/p>\n\n\n\n Importantly, most AKI-D data stem from high-income countries. The individual and societal impacts of AKI-D may be larger for patients in low- or middle-income countries, owing to resource-related challenges.<\/a><\/p>\n\n\n\n Pan et al1<\/a><\/sup> reported that AKD severity was not associated with long-term outcomes. Whether it is correct to infer that changes in kidney function in this period are not prognostically important or instead reflect the challenges of accurately measuring kidney function in the first 3 months after AKI is unclear. Serum creatinine is not a reliable marker of kidney function during the recovery period of AKI, often leading to kidney function overestimation. Better tools are necessary to determine severity of kidney disease during this time of increased risk.<\/a><\/p>\n\n\n\n The molecular and cellular mechanisms involved in maladaptive repair after AKI are active areas of research, and understanding them is necessary to develop strategies to promote proper repair and prevent the progression to CKD. Current data suggest that hemodynamic instability and hypotensive episodes are associated with higher risks of nonrecovery.7<\/a><\/sup> While prolonged fluid overload is associated with delayed kidney recovery, rapid fluid removal might cause hypotension and impair recovery too.<\/a><\/p>\n\n\n\n Interventions that slow the progression of CKD and reduce cardiovascular events might also improve long-term outcomes of AKI, but confirmatory trial data are lacking. Many therapeutic strategies that are known to benefit patients with CKD or cardiovascular disease may themselves contribute to an acute decline in kidney function. In patients with heart failure and reduced ejection fraction, treatment with RAAS-I significantly improves outcomes compared with patients not receiving RAAS-I treatment, despite an association between RAAS-I therapy and worsening kidney function.8<\/a><\/sup><\/a><\/p>\n\n\n\n Patients have described important health challenges after hospitalization with AKI that might impact long-term management and prognosis. A qualitative study of patients with AKI and their caregivers identified 3 important themes.9<\/a><\/sup> First, patients prioritized other comorbidities over their kidney disease; second, they lacked awareness of AKI as a potential long-term health issue; and third, they expressed anxiety from competing health demands. Another qualitative study identified 2 main barriers encountered by health care practitioners caring for patients after AKI.10<\/a><\/sup> First, AKI was perceived to be a complex condition to manage, often requiring clinical decisions that conflicted with the treatment of other comorbidities. Second, organizational boundaries were perceived as problematic for the coordination of AKI aftercare.<\/a><\/p>\n\n\n\nWhat Are the Causal Mechanisms for Poor Outcomes After AKI-D?<\/h2>\n\n\n\n
Are There Other Long-Term Risks After AKI-D?<\/h2>\n\n\n\n
Does AKD Severity Impact Clinical Outcomes?<\/h2>\n\n\n\n
Is it Possible to Prevent or Modify Long-Term Risks Following AKI-D?<\/h2>\n\n\n\n