In this cohort study conducted across two sites of a large tertiary centre in London, UK, we demonstrated a high AKI incidence of 39% in patients hospitalised for COVID-19. Acute kidney injury appeared to be an independent risk factor for mortality across all stages of severity, including stage 1.
To the best of our knowledge this is the largest patient series from the UK reporting on COVID-19 AKI, and is the only study to report historical baseline renal function and long-term renal outcomes. Hamilton et al, who also reported data from the UK, demonstrated a lower AKI rate of 20.3% among patients hospitalised with COVID-19, however there were no data available on historical renal function and admission creatinine was considered as baseline, which might have led to underreporting of AKI incidence (15). In our study one of the main determinants of increased AKI risk was pre-existing CKD.
AKI prevalence and incidence rates
Our findings of high AKI rates in patients with COVID-19 are consistent with large US patient series (32–46%) (5, 6, 16). Combined data from 13 New York (NY) hospitals (total n = 9657), demonstrated that AKI occurred in 39.9%, with stage 1 in 17% of the whole cohort, stage 2 in 8.7% and stage 3 in 14.2%(17). Nevertheless, some early reports, mainly from China, suggested considerably lower rates (0–7%)(1–4, 18, 19). A meta-analysis of 142 studies (total n = 49,048) reported a pooled AKI incidence of 28.6% (95%CI 19.8–39.5) among 20 studies based in the USA and Europe, and a much lower 5.5% (95%CI 4.1–7.4) among 62 studies from China (20). Several factors may account for the variation in reported AKI rates. In most studies demonstrating low AKI rates, the reported baseline CKD rates were lower (0.7–4.3%) (1, 3, 4, 18, 19) in comparison to ours and the large US patient series (5, 6, 16). It is difficult to determine, if these difference are related to variation in definitions and methods of recording CKD or patient characteristics among geographic areas. Furthermore, it has been hypothesised, that this might be due to considerable variation in the admission criteria between China and Europe and US, and, therefore, differences in COVID-19 severity among study populations(20). Lastly, there has been substantial inconsistency among definitions of baseline renal function used in previous studies (1, 4, 18, 21).
A novel finding of our study, is that the weekly AKI incidence rate increased over time to peak towards the middle of the study period and then declined reaching its nadir at the end of the observation period. This observation may be relevant to findings of Navaratnam et al, who suggested temporal changes of COVID-19 in-hospital mortality in England(22) with reducing rates towards May 2020. Several factors such as demographic, socioeconomic and clinical practice-related may have contributed and warrant further investigation on a broader scale.
ICU patient subgroup
The majority of patients admitted to ICU from our cohort sustained a stage 3 AKI (67%), while more than half of all ICU patients (54%) required RRT at some point. Some US patient series have reported AKI rates in ICU of more than 60% (61–78%) with RRT requirements for 35 to 50.9% of all patients (23–25); however, others reported lower rates (4 to 23%) (6, 26, 27). In our centre, an increased use of PD in ICU occurred during the study period due to a shortage of CVVHDF capacity (28).
It is possible that high AKI rates in this patient cohort are partly driven by a hyperinflammatory response, as suggested in a recent analysis indicating distinct biological response patterns in COVID-19, with renal injury linked to an enhanced inflammatory state (29).
Notably, the RRT rate in our ICU cohort is considerably higher compared to the contemporaneous (up to June 2020) rate reported by the Intensive Care National Audit and Research Centre (ICNARC) in the UK according to which, 26.2% among 9,132 patients with COVID-19 required RRT at some point (5.1% of which had pre-existing ESRD on dialysis) (30). It is not possible to ascertain what this discrepancy on RRT rates may be attributed to; however, it is worth noting that there was a considerably higher representation of black ethnicity in our ICU cohort of 30.5% as compared to 9.2% in ICNARC data.
AKI risk factors
The strongest independent determinant of AKI was the presence of pre-admission CKD defined as eGFR < 60 ml/min/1.73m2, which increased the risk of developing AKI more than three-fold. An association with pre-admission CKD has been confirmed in other reports, including a large meta-analysis of 142 studies (5, 16, 20). Chan et al. have similarly reported a 3-fold increase of risk for AKI in the presence of pre-admission eGFR < 60 ml/min/1.73m2among patients hospitalised with COVID-19 (n = 3993)(5), while Bowe et al suggested a step-wise increase in AKI risk with CKD stage in their retrospectively studied US Veteran cohort (n = 5216) (16). In addition to cardiac failure, pre-existing CKD was the only independent predictor for AKI reported by Kohle et al (31).
In our study, inpatient diuretic use was associated with a 79% higher AKI risk independent of demographics and comorbidities. Given the persisting uncertainties with regards to the management of COVID-19 AKI, caution with regards to the use of diuretics, especially in the presence of other AKI risk factors and especially background renal impairment may be prudent.
The changing AKI incidence rates in association with the link between inpatient diuretic use and AKI risk, may imply that a change in clinical practice and management of COVID-19 cases (in terms of fluid balance and diuretic prescription) may have partly played a role.
It is possible that early on during the pandemic, there was concern that COVID-19 patients were at risk of capillary leak linked to the hyperinflammatory state and consequently clinicians were cautious about excess fluid replacement. As the pandemic unfolded, the clinical community became rapidly aware of the high rates of AKI and clinical picture of volume depletion that evolved during the course of the disease. In the absence of evidence, the clinical community in the hospital shifted clinical practice during the first wave, adopting a more liberal fluid management strategy and actively withholding diuretics upon admission.
Black ethnicity and hypertension were also independent predictors of AKI in our study, which is consistent with other reports (6, 16). In a previous meta-analysis on AKI (non-COVID), black ethnicity was predictive of increased AKI rates at higher eGFR levels (32), while it has been suggested that the higher AKI (non-COVID) risk associated with black ethnicity, becomes less pronounced when adjusting for socioeconomic disparities(33). Interestingly, there was no link between high CKD-riskapolipopotein1 (APOL1) variants and AKI(33).
Impact of AKI on mortality and renal outcomes
In our study, the occurrence of AKI was independently associated with increased mortality at 30 days post-admission with a notably higher risk with increasing severity, with patients sustaining a stage 3 AKI carrying a 3-fold higher risk of death compared to their counterparts without AKI. The association of AKI with poor prognosis is well-described (34) and has been confirmed in COVID-19 (5, 16, 17, 19, 35). The majority (84.0%) of patients with AKI in our cohort that were discharged alive, recovered renal function to their pre-admission levels, while the respective percentage was lower (69.7%) for the most severe stage 3. This high recovery rate is in contrast to those reported by other studies (renal recovery to pre-admission levels 53–65% (5, 16)). None of our patients required RRT following discharge, while other studies have reported ongoing RRT requirements of 20% (16) and 30.6% (17) of the subgroup that required RRT during admission. With regards to longer term outcome, we present 3 to 6 month follow-up up data for the majority of survivors with AKI3. Among those, 30.7% presented a persistent decline in eGFR of > 15ml/min/1.73m2 at 3 to 6 months. Moreover, 21.5% without pre-existing renal impairment developed an eGFR of 60 < ml/min/1.73m2 (13). This suggests that the burden of CKD following COVID-19-related AKI may be substantial and under-diagnosed in the population as a whole, with significant future implications for both renal service provision and the associated higher risk of cardiovascular disease (36).