In this study, we report that 45% of COVID-19 patients admitted to intensive care for respiratory support developed an AKI and 20% required renal replacement therapy acutely for an average duration of 9 days. Overall hospital mortality for critically ill ICU patients with COVID-19 was 15%, compared to 25% in patients with AKI. All patients with AKI stage I and II had complete recovery to their baseline renal function and 92% of those who received RRT and survived had no ongoing requirement for RRT. Risk factors for the development of AKI were older age, preexisting diabetes mellitus and immunosuppression. AKI was associated with increased disease severity on admission (APACHE II and SOFA scores), persistently raised D-Dimer and more severe lymphopenia.
AKI is an independent risk factor for increased mortality in all critical illness [11,12]. The reported incidence of AKI among critically ill COVID 19 patients in other cohorts is approximately 20-30% and it is regarded as a marker of disease severity [13,14]. Reports from the USA and the UK suggest renal replacement rates of 25-31% in critically ill COVID-19 patients [3,15]. The incidence of AKI in our cohort was higher (44%) with 20% requiring renal replacement therapy.
Our finding of increased mortality in patients with AKI (25% vs 6.7%) is in keeping with other COVID-19 case cohorts [7,8,16,17]. Patients with AKI had more severe illness generally, required invasive mechanical ventilation, had higher illness severity scores, persistent lymphopenia and vasopressor support, suggesting that AKI is a marker of disease severity. Of our AKI completed cases that have been discharged home (n=28), mortality for all the AKI groups, Stage I, Stage II and the RRT group are 33%, 28.5% and 33% respectively. This is lower than the 60% national mortality in patients receiving RRT reported in the UK ICNARC outcome dataset . Patients in our RRT cohort had similar age and acute severity indices (APACHE II of 21, PaO2/FiO2 15.1kPa) with higher mechanical ventilation rate (100%) and 92% had vasoactive agents as advanced cardiovascular support suggesting this group is comparable to the ICNARC dataset .
Although the exact pathophysiological mechanism of AKI in COVID-19 remains elusive, it appears to be multifactorial. The angiotensin converting enzyme II (ACE-II) has been identified as a specific receptor for SARS-CoV-2 viral infection and is found in abundance in renal tubular epithelium and podocytes . Direct viral infection causing proximal tubular injury and disruption to podocytes has been demonstrated in postmortem studies with associated clinically documented presentation of hematuria and proteinuria . Moreover, there is local immune response with lymphocytic and CD8+ macrophage infiltration which may promote tubuloepithelial injury .
Hypercoagulability, microthrombi and microvascular injury have been extensively documented in patients with COVID-19 and may contribute to the development of AKI . The contribution of microthrombi formation in AKI has been found in postmortem findings, where there is erythrocyte stagnation with clot formation in the glomerular and peri-tubular capillaries in COVID-19 patients . Moreover, one study demonstrated that elevated D-Dimer level and complete failure of lysis at 30 minutes on a thromboelastogram are predictive of significant increase in the incidence of thromboembolism and a need for haemodialysis in critically ill COVID-19 patients . In our report, the development of AKI was associated with raised admission D-dimer levels and these abnormalities persisted in patients with AKI even after a week of ICU admission. This supports the fore-mentioned studies and highlights this maybe a potential contributor to the underlying pathophysiology of AKI in COVID-19 cases.
Interestingly, the use of diuretics was much more common in patients with AKI. Diuretics are often used in the intensive care setting to enhance a judicious fluid balance to improve oxygenation in patients with acute severe hypoxic respiratory failure. It is not clear whether the increased usage of diuretics contributed to the development of AKI or whether they were used to facilitate urine output and consequently improves fluid balance when AKI was already established. Similarly, AKI patients were more likely to be treated with corticosteroids. Corticosteroid use probably reflects a more severe disease process and it is not possible to make any direct conclusions regarding cause and effect from this study.
Our study has several limitations. Firstly, this is a small cohort study of patients admitted with COVID-19 characterised by acute hypoxic respiratory failure and needing respiratory support may not be representative of all hospitalised COVID-19 patients. Secondly, the laboratory testing for D-Dimer was not consistently measured for all patients and the missing values may have introduced bias. Moreover, there was an upper limit cutoff for D-Dimer values of 5000mg/l and as a result, we were unable to present the absolute laboratory values for levels beyond >5000mg/l. Thirdly, although our data is up to date as of 15th of June 2020; 22% of patients admitted with AKI remain in hospital so their final outcome is unknown which may impact our mortality estimates. Finally, we did not perform additional renal specific urine biological investigations to characterize the AKI which limits our ability to evaluate the mechanism of renal injury. Whilst we recognise these limitations, we were still able to identify factors associated with the development of AKI and outcome of AKI recovery. Reassuringly, all but one patient who recovered from their acute illness have also completely recovered from their acute kidney injury.