Renal resistive index is associated with acute kidney injury in COVID-19 patients treated in the intensive care unit

This was an observational cohort study conducted in six ICUs designated for COVID-19 patients (COVID-ICUs) at the Karolinska University Hospital, Stockholm, Sweden. Four ICUs were at one of two sites, and two at the other site. On specific dates, patients in each COVID-ICU were screened for participation. Inclusion criteria were infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) detected by a positive reverse transcriptase-polymerase chain reaction taken from upper or lower airways, admission to a COVID-ICU, and age ≥ 18 years. Exclusion criteria were end-stage renal disease (ESRD) before ICU admission, palliative phase of intensive care, ongoing irregular cardiac rhythm or treatment with extracorporeal membrane oxygenation (ECMO).

The study complied with the Declaration of Helsinki and was approved by the Swedish Ethical Review Authority. Requirement for signed informed consent was waived. A printed information sheet was sent to each patient or next of kin with the opportunity to retrospectively withdraw participation.

AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) classification as an increase in serum creatinine concentration (sCr) and categorized into three stages [21]. The highest sCr from ICU admission to the day of RRI measurement was compared to baseline sCr. Baseline sCr was defined as the last known value measured in a disease-free phase before admission. When no previous sCr value existed, hospital admission sCr was used. The AKI stages were defined as the following: stage 1, ≥ 1.5- to 1.9-fold increase or an absolute increase ≥ 26 μmol/l; stage 2, ≥ 2.0- to 2.9-fold increase; stage 3, ≥ 3.0-fold increase or an absolute increase > 354 μmol/l or initiation of RRT. The KDIGO urine output criteria were not used since hourly urine output was not always registered in the medical records. If the sCr elevation occurred more than 7 days before the RRI measurement and its value had returned to < 1.5-fold or < 26 μmol/l higher than from baseline, the patient was evaluated as having recovered from an AKI episode and was classified into the no AKI group. Oliguria at the time of RRI measurement was defined as urine output < 0.5 ml/kg ideal body weight/hour for 24 h regardless of diuretic drug administration [22]. Ideal body weight was calculated using the gender-specific Acute Respiratory Distress Syndrome Network formula [23]. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², ESRD was defined as eGFR < 15 mL/min/1.73 m², and eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [24]. For this, baseline sCr was used when classifying patients as having CKD or ESRD, and a combination of sCr and cystatin C was used when calculating eGFR at the time of RRI measurement. Comorbidities were considered present if documented in the patient’s medical record or if the patient was prescribed medication for the current state. The cardiovascular disease group included patients with cardiac failure, atrial arrhythmia, prior myocardial infarction or prior cardiac surgery.

All RRI measurements were performed by one of two operators (MR and OJ). Both operators had more than one year’s clinical experience of the RRI method. For each site a designated ultrasound device with a curvilinear probe of 1.0–6.0 MHz was used (GE Vivid S70N, US and GE Logiq E10, US at the two sites, respectively). The patients were examined in their ICU bed in supine or prone position depending on their respiratory requirements. Both kidneys were examined, and measurements were made on both or the most accessible side since the difference in RRI values between the right and left kidney has been shown to be negligible both in healthy and critically ill patients [9, 12, 17]. After obtaining a complete view of the kidney, color-Doppler was applied to visualize the global organization of intrarenal blood vessels. Pulse waved Doppler at the smallest possible width between 2 and 5 mm was used to measure flow velocities in an interlobular or arcuate artery in the upper, middle and lower kidney pole. The Doppler gain was set to obtain a clear outline of flow waves with minimal background noise. The pulse waved Doppler spectrum was considered optimal when at least three consecutive similar-looking waveforms for each pole were visualized. RRI was calculated for each pole as [(peak systolic velocity–end-diastolic velocity)/peak systolic velocity]. From the pole RRI values, a mean RRI was computed.

The following clinical data were collected for each patient at the time of RRI measurement: hemodynamic parameters, vasopressor requirements, sedatives dose and ventilator settings if mechanically ventilated. Severity of illness was graded on the day of measurement using the Sequential Organ Failure Assessment (SOFA) (originally the Sepsis-related Organ Failure Assessment) score [25]. Information on comorbidities, regular and current medication and laboratory data were collected from medical records.

Patient characteristics and variables are presented using frequencies and percentages for categorical data, and medians with interquartile range (IQR) and minimum/maximum (min/max) values for continuous data. Clinical characteristics of patients with or without AKI were compared using Fisher’s exact test for dichotomous variables and Wilcoxon rank-sum test for continuous variables. Median RRI between different groups were compared using the Wilcoxon rank-sum test. To elucidate potential confounding of the association between RRI and AKI, a multivariable logistic regression model was performed including RRI as a continuous and AKI as a dichotomous variable. Variables in our dataset that were associated with AKI with a p-value < 0.2 in bivariate logistic regression were selected for a manual forward selection procedure. Variables with the strongest association with AKI were included first, and variables that no longer were associated with AKI (p-value > 0.2) during forward selection were excluded. Remaining variables constituted the final model. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Goodness-of-fit of the model was assessed using the Hosmer–Lemeshow test. For all analyses a p-value < 0.05 was considered significant. The following variables had missing data: hospital admission sCr (n = 7 [14%]) and urine output at the day of RRI measurement (n = 2 [4%]). Missing data on height (n = 1 [2%]) were substituted with the median value according to sex. Statistical analyses were performed using Stata version 15.1 (StataCorp, College Station, US).

Median RRI in the study population was 0.76 (IQR 0.69–0.82, min/max 0.62/1.0). One patient had completely diminished end-diastolic blood flow resulting in an RRI of 1.0. Median RRI in patients with AKI was 0.80 (IQR 0.71–0.85, min/max 0.66/1.0) compared to 0.72 (IQR 0.67–0.78, min/max 0.62/0.84) in patients without AKI (p = 0.004) (Fig. 2). There was no difference in RRI between AKI stage 1 (median 0.76, IQR 0.71–0.83, min/max 0.67/0.88) or AKI stage 2 (median 0.79, min/max 0.79/0.80, n = 2) compared to no AKI (p = 0.347 and 0.134, respectively), but RRI was higher in patients with AKI stage 3 (median 0.83, IQR 0.71–0.85, min/max 0.66/1.0) compared to patients without AKI (p = 0.006) (Fig. 2).

RRI did not differ within the no AKI group when comparing patients who never had AKI (median 0.72, IQR 0.69–0.78, min/max 0.62/0.83) to patients with recovered AKI (median 0.68, IQR 0.67–0.81, min/max 0.65/0.84) (p = 0.621), but RRI was higher in the AKI group compared to both these groups (p = 0.015 and 0.021, respectively) (Fig. 3).

RRI was higher in oliguric patients (median 0.84, IQR 0.83–0.85, min/max 0.80/0.97) compared to non-oliguric patients (median 0.74, IQR 0.69–0.81, min/max 0.62/1.0) (p = 0.009) (Fig. 4).

Bivariate and multivariable logistic regression analysis is presented in Table 2. Possible confounders eligible for inclusion in the multivariable model are all variables presented in Table 1 except those that could be influenced by AKI and hence be part of a causal chain (ICU day, SOFA score, eGFR, oliguria, RRT, administration of diuretics). The following variables were omitted due to perfect prediction in the AKI groups (sex, cardiovascular disease, mechanical ventilation during ICU course, vasopressors during ICU course, tocilizumab, chloroquine phosphate, remdesivir, low-molecular-weight heparin). Variables included in the final model were RRI, BMI, CKD, vasopressors at measurement and administration of antiplatelet drugs. After multivariable adjustment, RRI was independently associated with AKI (OR for 0.01 increments of RRI 1.22, 95% CI 1.07–1.41). Goodness-of-fit had p = 0.705.