Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was responsible for a global pandemic affecting 769 million people worldwide, as of August 2023.1 Acute kidney injury (AKI) was reported in 30–50% of hospitalized patients with COVID-19, and nearly 20% required dialysis.2 COVID-19 patients with AKI had more severe disease, greater requirement of dialysis, in-hospital mortality, and less kidney recovery at discharge.3,4

AKI in patients with COVID-19 has a complex and multifactorial pathogenesis including endothelial dysfunction, complement activation, coagulopathy, and systemic inflammation. AKI is known to contribute to adverse short- and long-term outcomes, namely mortality, cardiovascular events and incident or progressive chronic kidney disease (CKD).5 Additionally, 10–20% of people with COVID-19 experience post-COVID-19 conditions, defined as a syndrome of persistent symptoms after infection. Post-COVID-19 can cause multi-organ damages with a wide spectrum of manifestations. Indeed, COVID-19-associated AKI has been linked with worse renal outcomes within the first months after discharge.6

At 3 months of follow-up, 16% of 313 AKI critically ill patients with COVID-19 developed CKD, and in survivors who had no renal recovery at discharge, the incidence of CKD was 44%.7

Lu et al. reported a higher incidence of dialysis dependence, death or eGFR decline ≥25% and cardiovascular events at 90 days of follow-up (p<0.05) in a cohort of 3296 COVID-19 patients with AKI.8 Salgueira et al. in 703 Spanish patients with COVID-19 described a more severe pattern of late onset AKI with greater need for renal replacement therapy (RRT).9

Also, in a cohort of 1612 patients, AKI associated with COVID-19 was associated with a greater decline of estimated glomerular filtration rate compared with AKI due to other causes, independent of underlying comorbidities or AKI severity (−16.7 (95% CI −43.4 to 10.0) vs −2.7mL/min/1.73m2/year (95% CI −26.8 to 21.4), p=0.01) on the first 6 months after hospital discharge.10

Whether this is associated with greater severity of AKI, or if SARS CoV2 infection has a direct effect on the kidney function decline is unknown and the long-term impact of COVID-19 in the kidney remains to be determined.

The purpose of this study was to evaluate the association of AKI and adverse renal events and mortality on a long-term follow-up in hospitalized patients with COVID-19.

We performed a single-center and retrospective study of hospitalized patients admitted to a Dedicated Unit for COVID-19 patients (UICIVE) at the Department of Medicine of the Centro Hospitalar Universitário Lisboa Norte (CHULN), in Lisbon, Portugal, between March 2020 and October 2020. Data collection was performed in March 2023.

The Ethical Committee approved of this study, in agreement with institutional guidelines and informed consent was waived, given its retrospective and non-interventional nature.

In this single-center and retrospective cohort of 409 hospitalized patients with COVID-19, we demonstrated that AKI was independently associated with the risk of long-term need for renal replacement therapy and/or renal function decline and/or mortality after hospital discharge.

In our study, AKI occurred in 60.4% of patients who survived the initial hospitalization and after two-years of follow-up 33.5% had a decline in kidney function or required kidney replacement therapy. This is in line with previously published literature although this cohort has the longest follow-up. Bowe et al. demonstrated that a group of 89,216 30-day survivors of COVID-19 had approximately 60% higher risk of MAKE than a non-infected control group of 1,637,437 patients.20 MAKE was significantly more frequent in patients who experienced AKI as well (70% vs. 46.9%, p<0.001). This is consistent with our cohort's results, as we reported 60.9% MAKE incidence. In fact, the two-year probability of MAKE in our cohort was 44.8% for AKI patients, while it was 39% for patients without AKI. On the other hand, Lu et al. when assessing 90-day MAKE incidence in COVID-19 survivors with AKI was only 22.6%. However, in the sub-group of patients with prolonged recovery of AKI MAKE incidence was significantly higher (22.6% vs 44.3%, p<0.001).21 In a cohort of 2212 patients, Atiquzzaman et al. also have shown the negative impact of COVID-19 infection in kidney function with a 3.4% decrease in eGFR after 1-year follow-up. This decrease is greater than expect for age adjusted decrease.22 Similarly, in our cohort, other than AKI, older age, CVD and CKD were also independent predictors of MAKE.

Regarding AKI severity, most patients who experienced MAKE were KDIGO stage 3, followed by KDIGO stages 1 and 2. These findings are compatible with previously published data which demonstrates the impact of AKI severity on long-term outcomes. Gu et al. reported a higher decrease on eGFR and reduced renal function in those with higher AKI stage.23 In a different study, Wan et al. demonstrated that adverse outcomes were strongly associated with increased severity of AKI.24

It is well known that AKI is a common complication of COVID-19 and has a complex and diverse etiology, being a result of both direct cytopathic effects and indirect mechanisms, such as ischemic injury from hypotension and hypoxemia, exposure to nephrotoxins, rhabdomyolysis, cytokine storm, activation and dysregulation of the angiotensin II pathway and complement system, endothelial dysfunction, abnormal platelet activation, hypercoagulation and microangiopathy.19,25,26

Some of the COVID-19 survivors may experience post-acute manifestations, with multiple system involvement. Studies on post-COVID-19 kidney events are limited in number and in follow-up duration.27,28 Our study adds to the literature by providing outcomes up to 2-years after hospital discharge, helping us understand the post-acute sequelae of COVID-19.

At the same time, it is vital to be aware of the risk of progression from AKI to CKD. Indeed, in our study, patients with AKI were older, had more CVD and CKD, which are some of the risk factors associated with poorer outcomes post-AKI, as well as AKI severity and duration. Another interesting finding of our study is that discharge serum creatinine was not associated with higher risk of kidney events after AKI. This has also been reported in previous studies suggesting that creatinine is an inaccurate marker to assess AKI recovery, reflecting fluid overload and muscle mass loss.29 Data from the NARA-AKI study demonstrated that creatinine and eGFR at a 3-month follow-up were stable or even increased after AKI most likely due to prolonged inflammatory and catabolic state.30 Haredasht et al. also reported that assessing eGFR using Cystatin C could detect more CKD events than creatinine in the follow-up of 101 AKI patients.31 As such, it is fundamental to identify high-risk patients and more precise biomarkers for CKD progression after AKI.

Simultaneously, AKI has been associated with an increased risk of cardiovascular events and short- and long-term mortality as demonstrated in this cohort.5 In a retrospective multicenter observational cohort of 12.891 hospitalized patients with a diagnosis of SARS-CoV-2 infection, Tan et al. reported a 50.5% incidence of AKI, as well as higher 1-year mortality in these patients (32.5% vs. 10.4%).32 In another study, Hadadi et al. demonstrated a 29.3% incidence of AKI. Furthermore, unresolved kidney injury at the time of discharge and AKI stages 2 and 3 were associated with an increased risk of mortality in the 10-month follow-up period.33 In a cohort of 2425 hospitalized patients with influenza and COVID-19, Strobenhn et al. showed a significant higher incidence of AKI and mortality in COVID-19 patients.34 Sullivan et al. in the ISARIC WHO CCP-UK cohort, demonstrated a 31.5% incidence of AKI and also reported greater 28-day mortality rates in these group of patients.35 Our study performed a long-term analysis with a mean of almost 20 months. Whether AKI contributes directly to the risk of mortality or is more frequent in patients with more comorbidities and thus higher mortality risk remains to be determined.

In the present study, some limitations must be acknowledged. First, the single-center and retrospective nature of the study may limit, in part, its generalizability. Second, the relatively small cohort of patients may have compromised, in part, the results.

Despite these limitations, our study has numerous strengths. Firstly, to our knowledge this study has the longest follow-up after COVID-19 investigating kidney outcomes. Secondly, even though we had a small cohort of patients, we were able to identify an association between AKI and long-term adverse renal events and mortality. Thirdly, we defined AKI according to the KDIGO classification using SCr criteria. Additionally, the current study addresses cause-specific mortality.

To conclude, AKI was independently associated with long-term kidney function decline and/or kidney replacement therapy requirement and/or mortality. This highlights the need for adequate follow-up care in these high-risk patients.

The Ethical Committee of ULS Santa Maria approved of this study, in agreement with institutional guidelines. The work was conducted in line with the Declaration of Helsinki.

There was no funding for this study.

The authors participated as follows: BMS and JG drafted the article. JLT participated in the collection of data. CC, CB, JO, JB, FB, JAF and JAL critically revised the manuscript.

Informed consent was waived given retrospective and non-interventional nature of the study.

There is no conflict of interest. The results presented in this paper have not been published previously in whole or part.

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