University of Groningen Acute Kidney Injury in critically ill patients Wiersema, Renske

(1)

Acute Kidney Injury in critically ill patients

Wiersema, Renske

DOI:

10.33612/diss.133211862

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date: 2020

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Wiersema, R. (2020). Acute Kidney Injury in critically ill patients: a seemingly simple syndrome. University of Groningen. https://doi.org/10.33612/diss.133211862

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

(2)

547452-L-bw-Wiersema 547452-L-bw-Wiersema 547452-L-bw-Wiersema 547452-L-bw-Wiersema Processed on: 25-8-2020 Processed on: 25-8-2020 Processed on: 25-8-2020

Processed on: 25-8-2020 PDF page: 93PDF page: 93PDF page: 93PDF page: 93

93

CHAPTER 6 Diagnostic accuracy of arterial

and venous renal Doppler

assessment for acute kidney

injury in critically ill patients:

a prospective study

Renske Wiersema, Thomas Kaufmann, Hilde N. van der Veen, Robbert J. de Haas, Casper F. M. Franssen, Jacqueline Koeze, Iwan C. C. van der Horst, Frederik Keus, SICS Study Group

(3)

94

Abstract Background

Renal Resistive Index (RRI) and Venous Impedance Index (VII) might be of additional value for diagnosing Acute Kidney Injury (AKI). The purpose of this study was to assess the diagnostic accuracy of RRI and VII for AKI.

Materials and methods

In the prospective Simple Intensive Care Studies-II (NCT03577405), we measured RRI and VII in acutely admitted adult intensive care patients within 24 hours of admission. AKI was defined by the Kidney Disease Improving Global Outcome (KDIGO) criteria. The primary outcome was persistent AKI, defined as non-resolved AKI on day three. We tested specificity, sensitivity and diagnostic accuracy of both RRI and VII for persistent AKI.

Results

In total, 371 patients were included of whom 123 patients (33%) had persistent AKI. RRI and VII did not differ between patients with and those without persistent AKI (p=0.08 and p=0.59). RRI had a moderate specificity (72%, 95%CI 66-78%) and low sensitivity (32%, 95%CI 24-41%) and VII had high sensitivity (93%, 95%CI 85-98%) and low specificity (11%, 95%CI 6-16%) for persistent AKI. Overall diagnostic accuracy of RRI and VII was moderate.

Conclusions

In acutely admitted critically ill patients, measures of renal perfusion by renal ultrasound were not different between patients with and without AKI, and show limited diagnostic accuracy for AKI.

Keywords: prospective study, ultrasound, acute kidney injury, diagnostic imaging, critical care, resistive index, Doppler

(4)

95

Introduction

One of the frequent complications of shock is Acute Kidney Injury (AKI), defined as a decrease in kidney function reflected by elevated serum creatinine, a decreased urine output or the need for Renal Replacement Therapy (RRT). In critically ill patients, AKI is associated with increased morbidity and mortality and its incidence varies between 30 and 60%.1_{Various underlying illnesses}

characterise critically ill patients with AKI, and therefore, it is likely that multiple mechanisms play a role in the pathophysiology of AKI.2

Diminished renal perfusion is one possible factor contributing to AKI 3,4_{, which can be caused}

several factors such as diminished arterial or venous flow in patients with circulatory shock. The possible harmful role of fluid overload or venous congestion in critically ill patients has been suggested in multiple cohorts5–9_{, but there is no diagnostic test to establish whether fluid overload}

has a direct impact on renal perfusion. Ultrasound has been used to assess renal perfusion.10–12

Three widely used measures to assess renal perfusion are Renal Resistive Index (RRI), Intra Renal Venous Flow (IRVF), and Venous Impedance Index (VII). RRI is the ratio of the velocities of arterial perfusion throughout the cardiac phases and it was reported to be associated with persistent AKI.13_{Recently, a multicentre study observed that the prognostic value of RRI for persistent AKI}

on day three might be limited.14_{The VII is a renal Doppler measurement to assess IRVF, which}

could potentially reflect renal venous congestion. In multiple studies including cardiac patients, measurements of renal venous perfusion have been shown to be associated with serum creatinine and overall patient prognosis.15–18_{In patients with diabetic nephropathy, VII was moderately}

associated with serum creatinine but had no additional value over RRI to evaluate renal function19_,

but no such studies have been performed in critically ill patients. This study aims to evaluate the diagnostic test accuracy of both RRI and VII for AKI in critically ill patients.

Methods

Design and setting

This study was a predefined sub-study of the Simple Intensive Care Studies-II (SICS-II), a single-centre, prospective observational cohort study designed to evaluate the prognostic and diagnostic value of repeated measurements of ultrasound in critically ill patients (NCT03577405).20

The local institutional review board approved the main study (M18.228393, 2018/203). This study was reported in adherence to the STARD guidelines.21

Objective

The primary objective was to assess the diagnostic accuracy of the RRI and VII for persistent AKI in a large heterogeneous cohort of critically ill patients.

(5)

96

Participants and study size

Participants were critically ill patients. The study size was dependent on patients included within SICS-II and the amount of available data. The inclusion criteria of the SICS-II were:

- Above 18 years of age; - Acutely admitted;

- Expected ICU stay of at least 24 hours Exclusion criteria were:

- Discharged within 24 hours;

- Non-traumatic neurological admission diagnosis (e.g., spontaneous intracranial haemorrhage);

- Absence of informed consent. Variables

We registered patient characteristics such as demographical data, comorbidities, and severity of illness scores at admission. Comorbidities were defined according to the Dutch National Intensive Care Evaluation (NICE) registry.22,23_{Patients were included as soon as possible, up to a maximum of}

24 hours after their ICU admission. We performed critical care ultrasound (CCUS) upon inclusion according to our protocol using the Vivid-S6 system (General Electric Healthcare, London, UK).20

We primarily assessed the right kidney as this is usually situated lower and more easily visualised, and the left kidney was assessed in case the right kidney could not be visualised. We registered the side where the kidney was measured, RRI, IRVF pattern (continuous, biphasic, monophasic), and the VII. The RRI was estimated in a renal arteriole at the corticomedullary junction near the renal hilum and defined by the peak systolic velocity minus the end-diastolic velocity divided by the peak systolic velocity (E-figure 1). The VII was estimated in a similar way, but in a renal vein and defined by the peak systolic velocity minus end-diastolic velocity divided by peak systolic velocity. If the IRVF pattern was monophasic, no VII was measured as it requires velocities in multiple phases for the calculation of a difference between these phases.

Training and image quality

CCUS examinations were conducted by trained researchers who were not involved in patient care. Training consisted of studying of theory, knowledge of the protocol and practical sessions with training on healthy individuals. The first 20 CCUS images and measurements of were supervised. At the end of the study, all images and measurements were validated or if needed remeasured by an expert radiologist who was blinded for other measurements and patient information.

Definitions

The index tests were the RRI and VII, and the reference standard was persistent AKI at day three. Transient AKI was defined as any AKI, which resolved within three days. Persistent AKI was defined as any AKI on day three.24_{AKI within this time frame is assumed to reflect renal injury during the}

diagnostic test as serum creatinine rises late after initial renal injury. In patients who had AKI but were discharged on or before day three, AKI was assumed to be transient. In patients who had

(6)

97 AKI and deceased on or before day three, AKI was assumed to be persistent. We defined AKI and its severity according to the Kidney Disease Improving Global Outcome (KDIGO) criteria based on serum creatinine, urinary output, and use of renal replacement therapy (RRT).25_{Baseline serum}

creatinine was defined as the lowest registered serum creatinine in the year previous to ICU admission. We used the MDRD formula to estimate baseline serum creatinine when unavailable. For urine output criteria, hourly registered data was used and grouped in six-hour time windows to assess AKI. The test performers did not know the results and cut-off points of both the index test and the reference standard.

Statistics

Continuous variables were reported as means (with standard deviations (SD)) or medians (with interquartile ranges (IQR)) depending on distributions. Categorical data were presented in proportions. Associations were calculated as odds ratios (OR) with 95% confidence intervals (CI). Student’s T-test, Mann-Whitney U test, or the Chi-square tests were used as appropriate. No missing data were imputed. We assessed whether the patients in whom no image was obtained had a higher risk of AKI, to assess potential bias in studies using renal ultrasound. The optimal cut-off point for RRI and VII was defined according to the optimal Youden’s J statistic using univariable analysis.26_{Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV),}

and overall accuracy of RRI and VII for persistent AKI were calculated to assess diagnostic accuracy. We performed two sensitivity analyses; we investigated whether diagnostic test performance was different when using previously described cut off values from the literature: 0.70 for RRI 27_and

0.38 for VII19_{, and we assessed whether the results of this study were robust when using different}

definitions of AKI. A two-sided p-value of <0.05 was considered statistically significant. Analyses were performed using Stata version 15 (StataCorp, CollegeStation, TX, USA) and R version R 3.6.0 (R Core Team, Vienna, Austria).

Results

Between 14 May 2018 and 10 July 2019, a total of 1010 patients were included in the SICS-II cohort. In total, 553 patients were included in the ultrasound cohort, and in 440 patients, measurements of renal ultrasound were obtained. Eventually, 371 patients were included with measurements of renal perfusion which were validated by the expert radiologist (Figure 1). The baseline characteristics of the 371 patients are shown in Table 1. A comparison of baseline characteristics of all patients and the patients included in this sub-study is shown in E-Table 1. Mean time to inclusion was 13 (±7) hours.

(7)

98

113 No measurement, reason: 56 No image obtainable 51 No abdominal US possible¥ 6 Other

371 Included in current analysis

627 Fulfilled inclusion criteria

383 Did not fulfill eligibility criteria for CCUS

1010 Included in SICS-II cohort

553 Underwent CCUS

74 Not included, reason:

46 No access within 24 hours 28 Continuous resuscitation or death

440 Renal CCUS performed

69 No measure of renal perfusion or insufficient quality

Figure 1. Flowchart of patient inclusion

Abbreviations: SICS = Simple Intensive Care Studies, CCUS = Critical Care Ultrasound, US = Ultrasound. ¥ Due to open wounds, bandages or severe abdominal pain.

(8)

99

Table 1. Characteristics of included patients

Abbreviations: SD = standard deviation, BMI = Body Mass Index, IQR = Inter Quartile Range. *Capillary refill time was considered prolonged if it was more than 4.5 seconds.

Acute kidney injury

Of the 371 included patients, 252 patients (68%) had some stage of AKI during the first three days of ICU admission, and 119 patients (32%) had no AKI. Of the patients with AKI, 146 patients (58%) had severe AKI; stage 2 or 3. Hundred and twenty-three patients (33%) had persistent AKI at day three and 129 patients (35%) had transient AKI. RRT was initiated in 12 patients (3%) within the first three days of ICU admission. In the 182 patients that were included in the ultrasound cohort but in whom no renal images could be obtained (Figure 1), persistent AKI incidence was higher (51% vs. 33%, p<0.001) (E-table 2). In univariable analysis, the absence of an image was significantly associated with persistent AKI (OR 2.1, 95%CI 1.4-2.9). This association remained significant in multivariable analysis (E-table 3).

Renal ultrasound

The right kidney was assessed in 342 patients (92%). RRI was obtained in 355 patients, and the mean RRI was 0.69 ± 0.08 for patients with AKI and 0.67 ± 0.08 for those without persistent AKI (p=0.08) (Table 2).

N = 371

Age, years (SD) 62 (14)

Gender, male (%) 244 (66)

BMI, kg/m2 _(SD) _{26 (5)}

Previous renal failure, n (%) 21 (6)

Diabetes mellitus, n (%) 64 (17) Liver cirrhosis, n (%) 13 (4) Admission type, n (%) Elective surgery 10 (3) Medical admission 241 (65) Emergency surgery 120 (32) At inclusion

Mechanical ventilation at inclusion, n (%) 234 (63)

RRT at the day of inclusion, n (%) 5 (1)

Use of vasopressors at inclusion, n (%) 196 (53)

Heart rate, BPM (SD) 84 (20)

Mean arterial pressure, mmHg (SD) 76 (13)

Subjectively cold temperature, n (%) 121 (36)

Prolonged capillary refill time sternum*, n (%) 35 (10)

Lactate, mmol/L (IQR) 1.3 (0.9-1.9)

Outcomes

Length of stay, days (IQR) 2.6 (1.6-5.4)

(9)

100

Table 2. Renal perfusion variables in patients with and without persistent AKI

Abbreviations: AKI, acute kidney injury; RRI, renal resistive index; IRVF, intrarenal venous flow; VII, venous impedance index.

Age and mean arterial pressure were associated with RRI, but lactate was not associated with RRI (p<0.001, p=0.001 and p=0.35, respectively, E-Table 4). Venous perfusion measurements were obtained in 252 patients, and the IRVF pattern was continuous in 128 patients (51%), biphasic in 108 patients (43%), and monophasic in 16 patients (6%). No difference was observed in IRVF patterns between patients with and without AKI (Table 2). No VII was obtained in those patients where the IRVF pattern was monophasic, and thus VII data were available in 236 patients, with a mean of 0.37 ± 0.11 for patients with AKI and 0.37 ± 0.12 for patients without AKI (p=0.59) (Table 2). Results were similar when using different definitions of AKI (E-table 5).

Diagnostic accuracy of renal ultrasound

The optimal cut-off for RRI was 0.74, where the sensitivity was 32% (95%CI 24-41%), and specificity was 72% (95%CI 66-78%). The PPV was 37% (95%CI 30-39%) and NPV was 68% (95%CI 65-71%) for persistent AKI, and overall diagnostic accuracy of RRI was 59% (95%CI 54-64%). The optimal cut-off for the VII was 0.23, where the sensitivity was 93% (95%CI 85-98%), specificity was 11% (6-16%), the PPV was 33% (95%CI 31-35%), the NPV was 77% (95%CI 57-90%) and the overall diagnostic accuracy of VII for persistent AKI was 37% (95%CI 31-43%) (Table 3). As diagnostic tests of both RRI and VII at optimal cut-off were moderate, we assessed whether a combined assessment of both tests would result in better diagnostic accuracy. Two-hundred and twenty-five patients had both RRI and VII assessed, and in 57 of these patients (25%), both were abnormal. Of these, 19 patients (33%) had AKI, implicating that diagnostic test accuracy was moderate (Table 4). Diagnostic test performances for RRI and VII were still moderate when using different, previously suggested cut-off values (E-Table 6).

EŽƉĞƌƐŝƐƚĞŶƚ</;ŶсϮϰϴͿ WĞƌƐŝƐƚĞŶƚ</;ŶсϭϮϯͿ ƉͲǀĂůƵĞ ZZ/ Ϭ͘ϲϳ;Ϭ͘ϬϴͿ Ϭ͘ϲϵ;Ϭ͘ϬϴͿ Ϭ͘Ϭϴ /Zs& ŽŶƚŝŶƵŽƵƐ ϴϰ;ϰϵйͿ ϰϰ;ϱϱйͿ Ϭ͘ϯϲ ŝƉŚĂƐŝĐŽƌ ŵŽŶŽƉŚĂƐŝĐ ϴϴ;ϱϭйͿ ϯϲ;ϰϱйͿ s// Ϭ͘ϯϳ;Ϭ͘ϭϮͿ Ϭ͘ϯϳ;Ϭ͘ϭϭͿ Ϭ͘ϱϵ

(10)

101

Table 3. Diagnostic test for perfusion variables

Abbreviations: AKI, acute kidney injury; RRI, renal resistive index; VII, venous impedance index, PPV; Positive predictive value, NPV; Negative predictive value

Table 4. Diagnostic test for both perfusion variables combined

Discussion

In a heterogeneous population of critically ill patients, the diagnostic accuracy of both RRI and VII for persistent AKI at day three after admission was moderate. Mean values of RRI and VII were almost equal, thus measures of RRI and VII cannot inform clinicians at admission on the likelihood of persistent AKI in individual patients. Interestingly, the absence of a usable image was associated with AKI, and this factor remained associated with AKI in multivariable analysis.

As more evidence points towards the role of venous congestion in AKI, it seems essential to investigate both arterial and venous perfusion measurements when studying the possibilities of renal ultrasound. This study is one of the first to assess both arterial and venous renal Doppler measurements in critically ill patients.

The diagnostic accuracy of RRI for AKI in our study is consistent with other studies. One study investigated the RRI in 351 critically ill patients and found similarly that prognostic and diagnostic accuracy of the RRI was moderate.14_{The method to define AKI and AKI incidence was similar, but}

Abnormal,

N Total, N Diagnostic test performance in %, (95% CI)

Sensitivity Specificity PPV NPV Diagnostic

accuracy RRI 103 (29%) 355 32 (24-41) 72 (66-78) 37 (30-39) 68 (65-71) 59 (54-64) VII 214 (91%) 236 93 (85-98) 11 (6-16) 33 (31-35) 77 (57-90) 37 (31-43) ďŶŽƌŵĂů͕ E dŽƚĂů͕E ŝĂŐŶŽƐƚŝĐƚĞƐƚƉĞƌĨŽƌŵĂŶĐĞŝŶй͕;ϵϱй/Ϳ ^ĞŶƐŝƚŝǀŝƚǇ ^ƉĞĐŝĨŝĐŝƚǇ WWs EWs ŝĂŐŶŽƐƚŝĐ ĂĐĐƵƌĂĐǇ ZZ/н s// ϱϳ;ϮϱйͿ ϮϮϱ Ϯϲ;ϭϲͲϯϴͿ ϳϱ;ϲϳͲϴϮͿ ϯϯ;ϮϰͲϯϵͿ ϲϴ;ϲϰͲϳϭͿ ϱϵ;ϱϮͲϲϲͿ

(11)

102

this study only included patients who were mechanically ventilated. Besides RRI, the authors also investigated the semi-quantitative evaluation of renal perfusion (SQP), which is a measurement to quantify the identification of renal vessels. The authors found that patients in which no renal vessels could be identified, but where it was possible to measure RRI using the SQP method. They found that this score was associated with AKI.14_{We similarly found that the inability to measure}

RRI, which could be due to a low SQP, was associated with AKI in multivariable analysis.

RRI can be influenced by many factors, as we showed for age and mean arterial pressure. It is plausible that besides age and mean arterial pressure, other variables are also associated with the RRI, such as diabetes, hypertension, or the use of specific medications, which we did not assess.28_{Evaluation in subgroups might yield different results, which may also point towards a}

more focused use of this variable. For such analysis however, larger sample sizes are needed. The value of VII as a marker for AKI has not previously been investigated in critically ill patients. One study investigated renal vein perfusion in 145 patients who underwent cardiac surgery.18

The study found that both portal vein pulsatility and IRVF were associated with AKI and proposed these two measurements as a marker of venous congestion. Although we did not measure portal vein pulsatility, we found that both IRVF and VII were not different in patients with and without AKI. A comparison of results is limited as in the other study, AKI was determined based on increases in serum creatinine, and a different, more homogeneous population was studied.18_Another

study investigated the renal venous stasis index as a new variable to reflect renal congestion in patients with diagnosed or suspected pulmonary hypertension.29_{This study showed that this}

venous ultrasound measurement was associated with worse renal function and that it provided additional prognostic information with regards to morbidity and mortality.30

Our hypothesis was that an assessment of venous perfusion potentially reflects renal congestion and the association between fluid overload and AKI but we demonstrated limited value of the VII. This hypothesis has been investigated using other proxies. One study investigated the additive value of central venous pressure (CVP) to the RRI in 124 septic patients and found that this increased prognostic value for septic AKI.12_{From our results, it seems that renal venous perfusion}

assessment is not associated with AKI in critically ill patients, which is in contrast to the results of previous studies in cardiac populations. This leads to the question whether renal vein assessment is useful in critically ill patients or whether other factors contributing to AKI in this population are more important than solely renal venous perfusion. Furthermore, our analyses showed that in patients in whom no renal perfusion measurements could be performed, the risk of AKI was higher. It is often unclear whether studies excluded patients in whom ultrasound measurements could not be obtained. We initially hypothesized this result could be explained by the fact that the inability to get an image is a proxy for previous renal failure and diabetes, but the association remained even after correcting for these factors.

(12)

103 Implications and generalizability

The most significant implication is that we demonstrate potentially limited value for the use of renal ultrasound to diagnose AKI in a heterogeneous single-center population of critically ill patients, which could be due to several reasons. First, renal ultrasound measures used in our study might not be sufficient to identify impairment in renal perfusion. Second, arterial and venous perfusion impairments might not be a causal factor in AKI and the main drivers of AKI might lay in different pathways, such as disturbances in systemic hemodynamic functioning. Third, a more useful measurement for assessment of venous perfusion other than VII might be needed.31

Limitations

This study has several limitations. First, we assessed the diagnostic accuracy of the perfusion variables using the presence of persistent AKI on day three, as serum creatinine often rises one to two days after the initial insult. We think, however, as we also used urine output criteria to diagnose AKI, that these numbers are reflective of the diagnostic accuracy at that moment and show that there was no difference in RRI or VII in patients with and without persistent AKI. Moreover, a sensitivity analysis showed that there was no difference in renal perfusion measurements between patients with or without AKI using other AKI definitions. Second, we assessed the association and diagnostic accuracy of the perfusion variables with persistent AKI, following examples from previous literature. It remains challenging to compare our results to other studies as the methods to diagnose AKI lead to various incidences, associations with outcome, and thus associations with proxies such as those investigated here. This is a limitation that is inherent to all studies investigating AKI. Third, the measurements were performed by trained researchers and not experts, which could affect the image quality and thus reliability of the measurements. This is why, for quality assurance, one expert radiologist validated all images and measurements and only approved measurements were included. Fourth, as literature concerning the VII in critically ill patients is scarce, it is difficult to compare whether the observed values reflect the expected values for VII. Moreover, in 32% of patients, no venous measurement could be obtained. Although it is known that obtaining ultrasound measurements in critically ill patients may be difficult, no feasibility studies exist that included the VII. This could have influenced our results. Further studies are warranted to assess the feasibility and meaning of venous perfusion measurements in critically ill patients.

Conclusion

In an unselected cohort of critically ill patients, RRI was not associated with AKI. VII, as a new potential measurement of renal congestion, was not different between patients with and without AKI. The diagnostic accuracy of both RRI and VII was low. Our results warrant external validation but raise the question whether evaluation of renal perfusion parameters by renal ultrasound will become a valuable tool for the diagnosis of AKI in the critically ill.

(13)

104

References

Hoste, E. A. J. & Schurgers, M. Epidemiology of acute kidney injury: how big is the problem? Crit. Care Med. 36, S146-51 (2008).

Ostermann, M. et al. Report of the first AKI Round Table meeting: an initiative of the ESICM AKI Section. Intensive Care Med. Exp. 7, 69 (2019).

Chen, K. P. et al. Peripheral Edema, Central Venous Pressure, and Risk of AKI in Critical Illness. Clin. J. Am. Soc. Nephrol. 11, 602–8 (2016).

Legrand, M. et al. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: A retrospective observational study. Crit. Care 17, (2013).

Rajendram R.and Prowle, J. R. Venous congestion: are we adding insult to kidney injury in sepsis? Crit Care 18, (2014).

Chen, X., Wang, X., Honore, P. M., Spapen, H. D. & Liu, D. Renal failure in critically ill patients, beware of applying (central venous) pressure on the kidney. Ann. Intensive Care 8, 91 (2018).

Vaara, S. T. et al. Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study. Crit. Care 16, R197 (2012).

Zhang, L., Chen, Z., Diao, Y., Yang, Y. & Fu, P. Associations of fluid overload with mortality and kidney recovery in patients with acute kidney injury: A systematic review and meta-analysis. J. Crit. Care 30, 860. e7-860.e13 (2015).

Wang, N. et al. Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study. Crit. Care 19, 371–374 (2015).

Ostermann, M., Hall, A. & Crichton, S. Low mean perfusion pressure is a risk factor for progression of acute kidney injury in critically ill patients – A retrospective analysis. BMC Nephrol. 18, 151 (2017).

Haitsma Mulier, J. L. G. et al. Renal resistive index as an early predictor and discriminator of acute kidney injury in critically ill patients; A prospective observational cohort study. PLoS One 13, e0197967 (2018). Song, J. et al. Value of the combination of renal resistance index and central venous pressure in the early prediction of sepsis-induced acute kidney injury. J. Crit. Care 45, 204–208 (2018).

Boddi, M. et al. Renal Resistive Index and mortality in critical patients with acute kidney injury. Eur. J. Clin. Invest. 46, 242–251 (2016).

Darmon, M. et al. Performance of Doppler-based resistive index and semi-quantitative renal perfusion in predicting persistent AKI: results of a prospective multicenter study. Intensive Care Med. 44, 1904–1913 (2018).

Nijst, P., Martens, P., Dupont, M., Tang, W. H. W. & Mullens, W. Intrarenal Flow Alterations During Transition From Euvolemia to Intravascular Volume Expansion in Heart Failure Patients. JACC Hear. Fail. 5, 672–681 (2017).

Iida, N. et al. Clinical Implications of Intrarenal Hemodynamic Evaluation by Doppler Ultrasonography in Heart Failure. JACC Hear. Fail. 4, 674–682 (2016).

Puzzovivo, A. et al. Renal Venous Pattern: A New Parameter for Predicting Prognosis in Heart Failure Outpatients. J. Cardiovasc. Dev. Dis. 5, 52 (2018).

Beaubien-Souligny, W. et al. Alterations in portal vein flow and intrarenal venous flow are associated with acute kidney injury after cardiac surgery: A prospective observational cohort study. J. Am. Heart Assoc. 7, (2018).

Jeong, S. H., Jung, D. C., Kim, S. H. S. H. & Kim, S. H. S. H. Renal venous doppler ultrasonography in normal subjects and patients with diabetic nephropathy: Value of venous impedance index measurements. J. Clin. Ultrasound 39, 512–518 (2011). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

(14)

105 Wiersema, R. et al. Observational Study Protocol for Repeated Clinical Examination and Critical Care Ultrasonography Within the Simple Intensive Care Studies. J. Vis. Exp. e58802 (2019) doi:10.3791/58802. Bossuyt, P. M. et al. STARD 2015: An updated list of essential items for reporting diagnostic accuracy studies. BMJ 351, (2015).

NICE Data Dictionary. https://www.stichting-nice.nl/dd/#49.

Arts, D., de Keizer, N., Scheffer, G.-J. & de Jonge, E. Quality of data collected for severity of illness scores in the Dutch National Intensive Care Evaluation (NICE) registry. Intensive Care Med. 28, 656–659 (2002). Perinel, S. et al. Transient and Persistent Acute Kidney Injury and the Risk of Hospital Mortality in Critically Ill Patients. Crit. Care Med. 43, e269–e275 (2015).

Kellum, J. A. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 17, (2013).

Perkins, N. J. & Schisterman, E. F. The Inconsistency of “ Optimal “ Cut-points Using Two ROC Based Criteria. Am J Epidemiol 163, 670–675 (2006).

Tublin, M. E., Bude, R. O. & Platt, J. F. The Resistive Index in Renal Doppler Sonography: Where Do We Stand? Am. J. Roentgenol. 180, 885–892 (2003).

O’Neill, W. C. Renal resistive index: A case of mistaken identity. Hypertension vol. 64 915– 917 (2014). Husain-Syed, F. et al. Doppler-Derived Renal Venous Stasis Index in the Prognosis of Right Heart Failure. J. Am. Heart Assoc. 8, e013584 (2019).

Husain-Syed, F. et al. Doppler-Derived Renal Venous Stasis Index in the Prognosis of Right Heart Failure. J. Am. Heart Assoc. 8, e013584 (2019).

Wiersema, R., Koster, G. & van der Horst, I. C. C. Clinical assessment of critically ill patients by whole-body ultrasonography. https://healthmanagement.org/uploads/article_attachment/icu-v18-i4-renske-wiersema-geert-koster-iwan-c-c-van-der-horst-clinial-assessment-of-crtically-ill-patients-by-whole-body-ultrasonography.pdf (2019). 20 21 22 23 24 25 26 27 28 29 30 31

(15)

106

Supplementary data

E-Figure 1. Measurements of RRI, IRVF and VII and applied formulas

E-Table 1. Baseline characteristics of included patients in this substudy compared to all patients in the SICS-II cohort

Abbreviations: BMI, body mass index; APACHE, Acute Physiology and Chronic Health Evaluation. Data presented as mean (SD), or number (percentage).

Excluded (N=639) Included (N=371) p-value

Age, years 60 (16) 62 (14) 0.12 Gender, male 386 (60%) 244 (66%) 0.090 BMI, kg m-2 _{27 (5)} _{26 (5)} _0.007 Diabetes 126 (20%) 64 (17%) 0.33 Liver cirrhosis 30 (5%) 13 (4%) 0.36 Mechanical Ventilation 296 (46%) 234 (63%) <0.001 Vasoactive medication 262 (41%) 196 (53%) <0.001 APACHE IV - score 69 (31) 71 (30) 0.35

(16)

107

E-Table 2. Multivariable analysis with not obtaining an image as risk factor for persistent AKI

Abbreviations: BMI, body mass index; APACHE, Acute Physiology and Chronic Health Evaluation; AKI, acute kidney injury. Data presented as mean (SD), or number (percentage).

E-Table 3. Multivariable analysis with not obtaining an image as risk factor for persistent AKI

Abbreviations: OR: Odds Ratio, CI: Confidence Interval. * Adjusted for age, body mass index and lactate.

E-Table 4. Associations between RRI and hemodynamic variables

Abbreviations: RRI, renal resistive index; CI, confidence interval

Coefficient (95%CI) p-value

Age, per 10 years 0.013 (0.007-0.019) <0.001

Mean arterial pressure, per 10 mmHg -0.012 (-0.018- -0.005) 0.001

Lactate 0.003 (-0.003-0.008) 0.349 EŽŝŵĂŐĞ;EсϭϴϮͿ /ŵĂŐĞ;EсϯϳϭͿ ƉͲǀĂůƵĞ ŐĞ͕ǇĞĂƌƐ ϲϰ;ϭϯͿ ϲϮ;ϭϰͿ Ϭ͘ϬϯϬ 'ĞŶĚĞƌ͕ŵĂůĞ ϭϮϮ;ϲϳйͿ Ϯϰϰ;ϲϲйͿ Ϭ͘ϳϳ D/͕ŬŐŵͲϮ _Ϯϴ;ϲͿ _Ϯϲ;ϱͿ _фϬ͘ϬϬϭ ŝĂďĞƚĞƐ ϱϰ;ϯϬйͿ ϲϰ;ϭϳйͿ фϬ͘ϬϬϭ >ŝǀĞƌĐŝƌƌŚŽƐŝƐ ϭϬ;ϲйͿ ϭϯ;ϰйͿ Ϭ͘Ϯϲ DĞĐŚĂŶŝĐĂůsĞŶƚŝůĂƚŝŽŶ ϵϯ;ϱϭйͿ Ϯϯϰ;ϲϯйͿ Ϭ͘ϬϬϳ sĂƐŽĂĐƚŝǀĞŵĞĚŝĐĂƚŝŽŶ ϴϲ;ϰϳйͿ ϭϵϲ;ϱϯйͿ Ϭ͘ϮϮ W,/sͲƐĐŽƌĞ ϳϵ;ϯϬͿ ϳϭ;ϯϬͿ Ϭ͘ϬϬϲ WĞƌƐŝƐƚĞŶƚ</ ϭϭϵ;ϲϱ͘ϰйͿ ϭϴϱ;ϰϵ͘ϵйͿ фϬ͘ϬϬϭ hŶĂĚũƵƐƚĞĚ KZ;ϵϱй/Ϳ WǀĂůƵĞ ĚũƵƐƚĞĚΎKZ;ϵϱй/Ϳ ƉͲǀĂůƵĞ /ŶĂďŝůŝƚǇƚŽ ŽďƚĂŝŶĂŶŝŵĂŐĞ ϭ͘ϴϵ;ϭ͘ϯϭͲϮ͘ϳϰͿ Ϭ͘ϬϬϭ ϭ͘ϱϳ;ϭ͘ϬϲͲϮ͘ϯϱͿ Ϭ͘ϬϮϲ ďŽĚǇŵĂƐƐŝŶĚĞǆĂŶĚ

(17)

108

E-Table 5. Renal perfusion measurements

Abbreviations: AKI, acute kidney injury; RRI, renal resistive index; VII, venous impedance index

E-Table 6. Diagnostic test for perfusion variables using cut-off values from literature, 0.70 for RRI and 0.38 for VII

No AKI (N=119) Any AKI (N=252) p-value

RRI (SD) 0.67 (0.08) 0.68 (0.08) 0.27

VII (SD) 0.37 (0.12) 0.37 (0.12) 0.62

No severe AKI (N=225) Severe AKI (N=146)

RRI (SD) 0.67 (0.08) 0.69 (0.09) 0.07 VII (SD) 0.38 (0.11) 0.36 (0.12) 0.46 ďŶŽƌŵĂů͕ E dŽƚĂů͕E ŝĂŐŶŽƐƚŝĐƚĞƐƚƉĞƌĨŽƌŵĂŶĐĞŝŶй͕;ϵϱй/Ϳ ^ĞŶƐŝƚŝǀŝƚǇ ^ƉĞĐŝĨŝĐŝƚǇ WWs EWs ŝĂŐŶŽƐƚŝĐ ĂĐĐƵƌĂĐǇ ZZ/ ϭϰϴ;ϰϮйͿ ϯϱϱ ϰϱ;ϯϲͲϱϱͿ ϲϬ;ϱϰͲϲϲͿ ϯϲ;ϯϭͲϰϯͿ ϲϵ;ϲϰͲϳϯͿ ϱϱ;ϱϬͲϲϬͿ s// ϵϴ;ϰϮйͿ Ϯϯϲ ϯϳ;ϮϲͲϰϵͿ ϱϳ;ϰϵͲϲϰͿ Ϯϵ;ϮϮͲϯϲͿ ϲϲ;ϲϭͲϳϭͿ ϱϬ;ϰϰͲϲϬͿ

(18)

(19)