This is the first study to describe RRI in patients with COVID-19. RRI was higher in patients with AKI compared to patients without AKI. RRI could distinguish patients with severe AKI from patients without AKI, and was higher in patients with an ongoing AKI episode compared to patients who had recovered from AKI earlier during the ICU course. Oliguric patients had higher RRI compared to non-oliguric patients.
Our results are in line with previous studies on mixed- or septic ICU patients, where RRI has been shown to be able to distinguish severe or persistent AKI from no or transient AKI [12, 13, 16, 23, 24]. In these studies, optimal RRI cut-off values for this discrimination have varied from 0.69 to 0.80. The median RRI of 0.80 in patients with AKI in our population must be considered high in comparison but may partly be due to the large proportion of patients with AKI stage 3 at the time of RRI measurement. Notably, patients without AKI in our study had higher RRI (median 0.72) compared to non-AKI patients in ICU populations without COVID-19 where reported values typically are lower than 0.65 [12, 14, 25]. It is not clear if elevated RRI in patients without AKI but infected with SARS-CoV-2 is a result of the infection itself, or if it reflects severity of illness as indicated by the long length of ICU stay as well as the high incidence of mechanical ventilation and vasopressor use in our population.
Proposed pathophysiological mechanisms of AKI in COVID-19 include hyperinflammation, altered regulation of the Renin-Angiotensin-Aldosterone-system with vasoconstriction and endothelial activation, hypercoagulability with development of microthrombi, and direct infection and damage of tubular cells and podocytes by SARS-CoV-2 via angiotensin-converting enzyme 2 receptors [2, 26, 27]. In ICU patients, unspecific kidney injury mechanisms such as hypo- or hypervolemia, use of nephrotoxic agents and hemodynamic changes due to mechanical ventilation with high levels of positive end expiratory pressures add to this burden . Several renal and extrarenal factors influence the RRI value, and in complex clinical settings the final profile of the flow wave and RRI are difficult to predict . The hypothesis that thrombi in the renal microcirculation may be a pathophysiological mechanism contributing to AKI in COVID-19 is supported by reports of high rates of thrombotic complications in hospitalized COVID-19 patients [29–31]. Both patients with and without AKI in our study presented with laboratory markers of hyperinflammation and deranged coagulation, but whether renal microthrombi contributed to the generally high RRI values observed in our population is unclear and needs further exploration.
Previous studies have in general focused on prediction of AKI from RRI measurements performed within the first day of ICU admission [12, 14–16, 23]. However, the ability of early RRI measurements to predict short-term AKI reversibility within three days recently has been challenged [32, 33]. Our finding of higher RRI in patients with an ongoing AKI episode compared to patients who had recovered from an AKI episode earlier during the ICU course suggests that RRI values rapidly decrease with recovered renal function. This indicates that RRI also might have a role later in the ICU- or hospital course for prediction of long-term renal recovery or progression towards CKD.
In our population of COVID-19 patients there was a strong association between elevated RRI and oliguria, and all oliguric patients had RRI values ≥ 0.80. One possible explanation could be oedema and increased pressure within the renal capsule. Elevated RRI values have been reported in animal models of increased renal interstitial pressure , and recently the venous impedance index calculated from measurements of intrarenal venous flow velocities have been investigated in ICU patients to assess the role of fluid overload on AKI . The fact that all oliguric patients in our population presented with very high RRI values suggests that RRI may have a role in the prediction of successful weaning from CRRT. A high incidence of circuit clotting has been described in COVID-19 patients on CRRT , and an RRI ≥ 0.80 in such a situation may indicate that restarting dialysis will be necessary while a lower value instead might suggest that pharmacological diuresis is appropriate.
As a non-invasive and repeatable bedside method, RRI is an interesting tool for the assessment of AKI in critically ill patients with COVID-19. The method has been demonstrated in different settings and centers to be easy and fast to learn even for non-experienced sonographers [17, 35], and should be applicable within POCUS-protocols for ICU clinicians even in the present resource scarce times of a pandemic.
Our study has several limitations. First, our study population was small, partly due to the fact that we used a convenience sample in two of the six COVID-ICUs. However, the included patients were severely ill with a large proportion having AKI, meaning the number of patients with AKI was in line with many previous RRI studies on ICU populations [15, 24, 35]. Second, RRI measurements were performed at different time points in different patients, and most of the measurements were made late in the ICU course. During the peak of the pandemic in Sweden, the involved University Hospital functioned as a referral hospital and many patients were transferred to its ICUs from other hospitals when they already had received several days of intensive care. This meant there was a delay from ICU admission to accessibility in some of the patients. However, it also meant that most of the measurements were performed in a hemodynamically stable phase reducing the influence of hemodynamic factors on the RRI value as well as allowing the comparison of RRI in patients with or without recovered AKI episodes. Third, intra- and interobserver variability for the operators were not investigated. Our group has previously shown that RRI measurements by inexperienced sonographers were reliable, accurate and precise compared to an expert after only a brief training session , and both operators in our study were experienced with the RRI method. Lastly, our study was affected by some of the well-known pitfalls in AKI-research. The use of hospital admission sCr as baseline level in patients in whom pre-admission sCr was missing might have resulted in an underestimation of the AKI-incidence. Further, using sCr decline to define recovery from an AKI episode could in patients with muscle wasting during a prolonged ICU course lead to overestimation of renal function recovery . However, we used eGFR-calculations based on a combination of sCr and cystatin C at the time of RRI measurement and still observed a difference in estimated renal function between patients classified with or without AKI, suggesting any such misclassification was negligible.