Abstract : 
Development of a hemodialysis model in rats with septic acute kidney injury

Introduction / Rationale :
Adapted organ support techniques are needed to enhance reliability of preclinical animal experiments in the intensive care setting (Guillon, Annals of Intensive Care-2019). A few renal replacement therapy (RRT) models have already been developed in rats, mostly hemodialysis in chronic kidney disease models or hemofiltration techniques in sepsis experiments. Mounting evidence from clinical (Gaudry, NEJM-2016) and histopathological studies suggest that RRT for acute kidney injury (AKI) could impair renal recovery by acting as a 'second hit' leading to a maladaptive repair of tubular epithelium.
We aimed to study this hypothesis in a hemodialysis model in rats with septic AKI.

Méthodes / Patients and Methods :
On day 1, Sprague Dawley rats were injected with lipopolysaccharide or placebo (NaCl 0.9%) intraperitoneally. On day 2, anesthetized rats underwent femoral artery catheterization for hemodynamic parameters monitoring. At the same time, one femoral vein and one carotid artery were catheterized for arterio-venous sterile extracorporeal circulation with or without passing through a miniature sterile Polyester Sulfone hemodialyzer (20 cm2 surface, 50 kDa pores, MicroKros®) filled with dialyzate liquid in the outer compartment (Table 1). Vessels were ligated after the procedure and rats allowed to awaken. On day 3, rats were sacrificed.

Résultats / Results :
All rats injected with lipopolysaccharides O127:B8 10 mg/kg survived at day 2.
Anesthesia was much challenging: Ketamine + Xylazine and Tiletamine-Zolazepam + Xylazine required induction and maintenance intraperitoneal injections. These medications induced important hemodynamic parameters fluctuations and high mortality. Isoflurane gas inhalation enabled better stability, less hypothermia and quick awakening. Adequate temperature was controlled with a heating pad during the procedure and an incubator after. Supine position was maintained. The whole circuit was anticoagulated with 1 ml of heparinized saline 100 UI/ml, since clots occurred in the absence of anticoagulation and bleeding when higher dosing was used. Circuit (< 1,5 ml including dialyzer) was filled with saline solution before initiation, and total restitution of blood at the end of the experiment prevented any blood transfusion requirement. Hematocrit was determined at beginning (50%) and end of experiment (40%). A peristaltic pump provided a blood flow rate of 1.0 mL/min, (higher rate was not tolerated) for 2 hours. Of note, rats who underwent sham procedure (vessels ligature only) survived and did not display AKI. Circulation of a counterflow dialysate in the dialyzer is planned but has not been performed yet.

Discussion / Discussion :


Conclusion / Conclusion :
This hemodialysis system for rats is feasible at a reasonable price and might help research involving RRT in either CKD or AKI.
 

Abstract : 
Incidence and renal prognosis of positive antibiotic associated crystalluria in infective endocarditis patients

Introduction / Rationale :
Infective endocarditis (IE) is a rare disease characterized by an high mortality.High-dose antibiotic has long been recognized to induce acute kidney injury (AKI) through various routes of injury. Next to acute interstitial nephritis, antibiotic-associated crystal (AAC) nephropathy has been increasingly acknowledged as a cause of severe AKI.
We aimed at describing the prevalence of AAC of patient admitted and treated for suspected IE, identifying factors associated with positive AAC and assessing renal prognosis of positive AAC patients.

Méthodes / Patients and Methods :
All patients admitted consecutively for suspicion of IE to the cardiology unit of Mondor hospital (APHP, France) between 2017, June, 1st and 2018, June, 1st were included in the present study. IE was defined according to the modified Duke criteria. Urinary samples was collected during the first week of hospitalization and transferred to Tenon hospital (APHP, France) laboratory within 4h.
Outcome principal was the occurrence of AAC defined by the observation of antibiotic crystal formation with combining polarized microscopy and infrared spectroscopy. Secondary outcomes were the occurrence of AKI stage ≥ 2 according the KDIGO classification and the estimated glomerular filtration rate (GFR) estimating by MDRD equation at day-14.

Résultats / Results :
34 patients were included in the analysis. Most of them were men (71 %) and the median age was 70 [62-77] years. Pathogen was identified in 82% of patients. The most frequently identified pathogen was Streptococcus. Modified DUKE criterias defined IE as definite in 21 (64 %), possible in 4 (12 %) and suspected in 9 (24 %) cases.
First line antibiotherapy was composed by Amoxicilline (94%), Gentamycine (87%) and Cefazoline (37%).
65 crystallurias were performed within a median time 5[3-6] days. AAC was observed in 18 urinary analysis from 14/34 patients. Multivariate logistic mixed effect analysis identified blood amoxicillin concentration (OR=1.02[1.01-1.05]) and urinary pH (OR=0.79[0.62-0.94]) as risk factors to AAC.
Severe AKI occurred in 18 (53%) patients. Statistical trend was observed with the occurrence of AAC (p=0.07). Estimated GFR was below to 60mL/min/1.73m2 at day 14 in 32% of patients. AAC was not associated with a eGFR < 60mL/min (p=0.10). After exclusion of patients with CKD, we observed a statistical trend with the occurrence of AAC (p=0.08).

Discussion / Discussion :


Conclusion / Conclusion :
AAC is a common complication of patients treated by high dose of antibiotics for suspected IE. Our results suggest of potential renal short term impact of AAC.
 

Abstract : 
Cytogenetic Abnormalities and Risk for Acute Kidney Injury in Critically Ill Patients with Acute Myeloid Leukemia (AML)

Introduction / Rationale :
Acute kidney injury (AKI) is a challenging organ dysfunction in hematology patients. Indeed, optimal management relies on patient’s ability to receive the best standard of care and optimal chemotherapy regimen, which may not be possible in case of severe AKI. Moreover, in ICU patients with high tumoral burden, patients with baseline AKI are at high risk of tumor lysis syndrome (TLS), need for renal replacement therapy (RRT), delayed renal recovery and increased mortality. In patients with aggressive hematologic malignancies, risk factors for AKI have been previously identified. However, in critically ill patients with AML, the risk for AKI across different AML French-American-British (FAB) classes and on cytogenetic abnormalities has never been assessed.

Méthodes / Patients and Methods :
Patients were classified based on cytogenetic data according to the WHO classification into three groups (favorable, intermediate, or unfavorable). AKI was defined based on KDIGO definitions using creatinine level at ICU admission and need for RRT. A Cox proportional-hazards model was used to identify factors associated with long term survival.

Résultats / Results :
Among the 144 AML patients (age 58y [45-68], 60%men, performance status 1 [0-2]), 54 (37.5%)) were AML4 or 5, 24 (16.7%) were AML3, and 66 (45.8%) had other FAB classes. According to the WHO-cytogenetic classification, 13 (9%) patients were in the favorable group, 77 (54%) in the intermediate group, and 30 ( 21%) in the unfavorable group. AML3 was found in 24 (16.7%) patients. Patients were untreated in 78.5% of the cases and half of them were hyperleukocytic. SOFA score was 5 (4-9) at admission. Baseline creatinine was 88 (80-97). Based on KDIGO, 68 (47.2%) patients had no AKI, 30 (20.8%) had a stage 1, 17 (12%) a stage 2 and 29 (20.1%) a stage 3 AKI. Throughout the ICU stay, septic shock occurred in 31(21%) patients, 23(16%) presented TLS, 67(46%) received vasopressors, 42(29.2%) RRT, and 4 (31%) died in the ICU.
By multivariable analysis, factors associated with AKI were male gender, poor performance status, hyperleukocytic AML, SOFA score, DIC and the WHO-cytogenetic classification (HR 2.60 [2.17-96.7] for the intermediate class, 1.98 [1.18-69.7] for the unfavorable class). FAB and WHO cytogenetic-based classifications were not significantly associated with mortality.

Discussion / Discussion :


Conclusion / Conclusion :
Half the critically ill AML patients present with AKI, a condition that is independently associated with increased mortality. Patients in the intermediate and unfavorable WHO-cytogenetic groups are at high risk of AKI, independently of leukocytosis and severity. Studies to elucidate the mechanisms pertaining AKI in these specific subgroups are warranted.
 

Abstract : 
Do Renal Resistive Index (RRI) measurement predict renal function evolution in critically ill patients with stage 2 Acute Kidney Injury (AKI)?

Introduction / Rationale :
The place of Doppler-derived Renal Resistive Index (RRI) as a potential renal function predictor remains controversial because of its low specificity. Patient’s vascular compliance is known to affect this measurement. Moreover, the optimal timing for the most accurate prediction is unknown.

Méthodes / Patients and Methods :
This prospective observational study included 57 patients where RRI was measured when they met at least stage 2 Acute Kidney Injury (AKI) according to KDIGO criteria. Risk factors, severity score, presumed AKI aetiology (hypoperfusion, sepsis, congestion, vascular glomerular dysregulation), renal evolution, Renal Replacement Therapy (RRT) requirement, clinical and biological data were recorded. Patients were classified according to their RRI value (cut off: 0.70) for comparison.

Résultats / Results :
Initial RRI measurement was higher than 0.7 for 39 patients (68%).
There were no significant relationship between RRI and past medical history or severity score.
We observed a significant negative correlation between RRI and diastolic arterial pressure (p = 0.004) and heart rate (p = 0.004) as it could be expected by RRI formula. An increased RRI was associated with higher potassium (p = 0.019) and higher creatinine levels (p = 0.042).
Although not significant, we found a higher rate of subsequent RRT in the high RRI group (23% vs 6%, p = 0.146).
Over the first 3 days, fluid balance was significantly different between groups (2217 ml vs –1314ml respectively for low and high RRI group, p = 0.017). Since standard of care were similar, this suggests different fluid volume status between the two groups. In the low RRI group, the cause of AKI could predominantly be prerenal since positive fluid balance was not explained by more severe AKI with refractory oliguria as shown by the low RRT rate. Nevertheless, we did not observed any relationship between RRI and the evolution of serum urea or creatinine levels, nor with the presumed aetiology of AKI.

Discussion / Discussion :


Conclusion / Conclusion :
When focussing on the first RRI measurement once stage 2 AKI was reached, RRI ≤ 0,7 seems to be in favour of prerenal and transient renal dysfunction even if this is not supported by creatinine serum evolution.
 

Abstract : 
Doppler based resistive index measurement in ICU patients and influence of inter-operator variability: Results of a multicenter cohort study

Introduction / Rationale :
Clinical data regarding factors that may influence Doppler-based resistive index (RI) at bedside are limited. Moreover, influence of operator has poorly been assessed.
This study aimed at evaluating clinical characteristics associated with RI at bedside and to delineate influence of inter-operator variability as this regard.

Méthodes / Patients and Methods :
Post-hoc analysis of a multicentre prospectively collected dataset. Adult patients requiring mechanical ventilation were included. Patients with severe chronic renal dysfunction or known renal artery stenosis were excluded. AKI was defined according to KDIGO definition. Renal Doppler was performed at study inclusion. Operators involved in this study were anonymised.
Results are reported in n (%) or median (IQR). Adjusted factors associated with AKI development were assessed using mixed linear regression model with the operator as random effect on the intercept.

Résultats / Results :
Overall, 351 patients were included in this study, including 149 patients with AKI stage 1 (42.5%), 33 patients with AKI stage 2 (9.0%) and 51 patients with AKI stage 3 (14.5%). Median age was 62 years (IQR 51-70), and 129 were of female gender (36.8%). Vasopressors was required in 184 patients (52.5%).
RI was associated with AKI severity, with a RI of 0.65 (0.59-0.70) in patients without AKI and increasing steadily to 0.72 (0.62-0.78) in patients with AKI stage 3.
After adjustment for confounders, factors independently associated with RI were age (estimate per year: 0.001, sd: 0.0003; p<0.001), case mix (emergency surgery estimate (vs. medical): -0.06, sd:0.03; p=0.03), hypovolemia at ICU admission (estimate : 0.03, sd:0.02; p=0.02), underlying cardiac comorbidity (estimate : 0.05, sd:0.02; p=0.002), use of norepinephrine (estimate : 0.03, sd:0.0; p=0.007), and AKI stage 3 (vs. no AKI) (estimate : 0.04, sd:0.02; p=0.02). When forced in the final model, mean arterial pressure, pulsed pressure, plateau pressure, heart rate, sepsis were not selected.
Operator was found to influence significantly RI in the mixed model (figure 1a; mean OR 0.03 [0.01-0.05]; p<0.001). To further depict the influence of inter-operator variability, adjusted changes in RI according to age (1a) and AKI KDIGO stage (1b) are reported for each operator (each line depicting an operator).

Discussion / Discussion :


Conclusion / Conclusion :
Our study suggests that Doppler-based RI in critically ill patients is influenced by patients’ case-mix, age, underlying dehydration or shock, cardiac comorbidities, and AKI severity. Our study confirms and illustrates a strong inter-operator variability of RI measurement in ICU that persists after adjustment. Whether this inter-operator variability impairs RI reliability and usefulness at bedside deserve to be more carefully assessed.
 

Abstract : 
Echocardiographic follow-up of right ventricular dysfunction is the best way to evaluate cardiorenal syndrome (CRS) in ICU.

Introduction / Rationale :
Type 1 Cardiorenal syndrome (CRS) is defined by acute decompensated heart failure (AHF) leading to secondary acute kidney injury (AKI) due to persistent congestion. Diagnosis is often difficult and relies on compatible clinical history, symptoms and biology. There are currently no studies evaluating the reliability of transthoracic echocardiography (TTE) as a diagnostic tool in CRS. Therefore, the aim of this study was to assess quantitative and qualitative echocardiographic parameters in patients with CRS in the ICU at baseline and after appropriate care (pharmacologic therapy, with or without additional ultrafiltration).

Méthodes / Patients and Methods :
We conducted an observational, prospective, single-center study in the ICU department of a general hospital. Patients admitted in the ICU and presenting with type 1 CRS were included. Diagnosis of CRS was made based on clinical context, biology and confirmed by two attending physicians (nephrologist and cardiologist). Patients presenting with other causes of AKI were excluded. Transthoracic echocardiography was performed at baseline and at day 7 after treatment by the same trained operator for the same patients. We report various echocardiographic indices of right and left ventricular function, filling pattern and venous pressure at these two timepoints.

Résultats / Results :
A total of 27 patients were included in this study. At baseline (D0), 96.3% of patients had signs of congestion (IVC dilation >2 cm), 76 % had an altered S-wave (<11.5 cm/s), 72.73% had an altered TAPSE (<15 mm), 85.19% had an elevated RV/LV surface ratio (>0.6). Between baseline and D7, under appropriate management, IVC size significantly decreased ([-1.8 ; - 0.3] p<0.001), the number of patients with an elevated RV/LV diameter ratio (>0,6) also decreased (OR [IC 95%] = 0.087 [0.02 ; 0.37] p<0.001), weight decreased (4.1kg (5.24) p<0.001), whereas natriuresis significantly increased (47.11mM/ml (45.55) p<0.001), and the amount of vasopressors support decreased (- 0.04 ug/kg/min [-5.9 ; 0.46] p<0.001). Other parameters including creatinine level (-14.33uM/L [-42.02 ; 13.35]), cardiac index (+0.35L/min/m² [-0.05 ; 0.73]), and S-wave velocity (0.32cm (2.67)) showed non-significant changes.

Discussion / Discussion :


Conclusion / Conclusion :
Main echocardiographic findings at baseline in patients with type 1 CRS consist of a right ventricular dysfunction associated with a state of increased venous pressure and congestion in the form of an IVC dilation. We report that weight, RV/LV diameter ratio, and IVC diameter might constitute good follow-up parameters to monitor treatment response.
 

Abstract : 
Is citrate required for heparin-free intermittent hemodialysis in critically ill patients?

Introduction / Rationale :
Critically ill patients are at higher risk of bleeding but also dialysis filter clotting (inflammatory state). Intermittent hemodialysis with calcium-free citrate-containing (0.8 mmol/L) dialysate (CafCit-IHD) recently emerged as a new safe and simple alternative to continuous renal replacement therapy allowing heparin-free extended dialysis sessions (>5 hours). In this study, we aimed to answer to two issues still unresolved: (i) can citrate contained in the dialysate accumulate and lead to citrate intoxication in patients with liver disorders, and (ii) can citrate be avoided using citrate- and calcium-free dialysate (CCF-IHD)?

Méthodes / Patients and Methods :
Monocentric retrospective study. Among the 450 sessions performed with CafCit-IHD, the 20 IHD sessions (18 critically ill patients) with citrate measurement available before and after the dialysis filter were reviewed. Estimation of the liver clearance was performed using the Picco Lemon® system (Pulsion). In addition, 8 sessions performed using CCF-IHD were reviewed.

Résultats / Results :
All the patients had liver disorders (post-liver transplantation period n=2; cirrhosis with Child >A6). Among the eighteen CafCit-IHD patients, fifteen (75%) and six (30%) received mechanical ventilation or vasopressive drugs, respectively. The median time of the dialysis session was 5 hours [2-5], with hourly ultrafiltration rate of 400 mL (one premature termination not related to dysfunctional catheter). In all patients, ionized calcium (iCa) decreased below 0.40 mmol/L after the filter, whereas post-filter calcium reinjection according to ionic dialysance led to a stable pre-filter (i.e. patient) iCa. Median citrate concentrations were all below 0.8 mmol/L after the filter (minimal concentration to obtain anticoagulation 3 mmol/L) and all except one below the normal value (< 125 mol/L) before the filter. During all the sessions, ionized to total calcium ratio was below 2.1 and the strong ionized gap decreased. When available (n=7), no correlation could be identified between serum citrate concentration and liver clearance. Last, in 8 CCF-IHD sessions performed in critically ill patients, no premature termination occurred (median time of the sessions 5 hours) and post-filter iCa also decreased below 0.45 mmol/L.

Discussion / Discussion :


Conclusion / Conclusion :
No citrate accumulation could be identified in critically ill patients (even with liver disorders) and receiving extended dialysis sessions (5 hours or more) using calcium-free citrate containing-IHD. Interestingly, we demonstrated that citrate is not required to obtain optimal regional anticoagulation (i.e. post-filter iCa < 0.45 mmol/L), and a citrate- and calcium-free dialysate could be a safe alternative.