American Journal of Respiratory and Critical Care Medicine

To the Editor:

Acute kidney injury (AKI) complicates the clinical course of 5–10% of hospital admissions and up to 50% of patients admitted to ICUs (1). Continuous renal replacement therapy (CRRT) has become the most widely used form of renal support in critically ill patients (2), as it allows continuous and controlled removal of fluids and is better tolerated hemodynamically than traditional intermittent dialysis. The requirement for intravascular access and artificial circuits may increase the risk of infection. However, there are no studies analyzing the incidence and characteristics of infections in critically ill patients with CRRT, or the implications for outcome. Therefore, we sought to examine these questions using data from the RICH (Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation) trial (3).

In the RICH trial, we found that among critically ill patients with AKI receiving CRRT, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter lifespan (3). Interestingly, compared with heparin, regional citrate resulted in significantly more new infections (defined as new culture-proven infection since start of dialysis in patients with preexisting infection but with a pathogen other than baseline or a new infection in patients without an infection at baseline after initiation of CRRT up to the end of ICU stay or Day 28, whatever occurred first; we did not differentiate clinically proven infections from colonization). Regarding the source of infection, there were no significant differences between the randomized groups with regional citrate and systemic heparin anticoagulation, neither in the incidence nor in the time to new onset of bacteremia, pneumonia, urinary tract infection, or other sources of infection. Here, we show that patients who developed new infection had a higher mortality (Table 1 and Figure 1) (hazard ratio, 1.45 [95% confidence interval (CI), 1.13–1.87]; P = 0.004; time-dependent Cox regression adjusted for the type of anticoagulation). However, for patients developing new infection during dialysis-dependent AKI, mortality was similar for citrate and systemic heparin (P = 0.597). To investigate which factors were associated with the development of infection in patients with AKI receiving CRRT, we investigated different factors related to preexisting illness (diabetes or chronic kidney disease), acute illness severity (mechanical ventilation, vasopressor use, sequential organ failure assessment score, and hypophosphatemia), and renal replacement therapy (catheter location, fluid balance, modality, post-filter Ca2 + ion concentrations, and type of calcium solutions). None of these factors were associated with new onset of infection. Each patient’s mean filter lifespan was calculated as the average lifespan of multiple filters that may have been used. In patients without new onset of infection, all filters that were used up to the end of the primary CRRT were included. In patients experiencing a new infection, the averaging was restricted to filters that were used in the period up to (and including) the onset of infection. We identified that longer mean filter lifespan was associated with an increased infection rate. Increasing mean filter lifespan by 10 hours increased the infection rate by 21% (odds ratio [OR], 1.21 [95% CI, 1.11–1.31]; P < 0.001; adjusted for the type of anticoagulation). With a mean filter lifespan of more than 48 hours, the rate of infections was significantly increased compared with 48 hours or less (156 of 213,  73%, vs. 201 of 362, 56%; OR, 1.99 [95% CI, 1.36–2.91]; P < 0.001; adjusted for the type of anticoagulation). If patients with the same total filter lifespan were compared, those patients with more frequent filter changes (consequently shorter mean filter lifespan) had a lower risk of new infections than patients with less frequent filter changes and a longer mean filter lifespan. However, the type of anticoagulation did not affect the infection rate significantly when controlling for the mean duration of filter use (adjusted OR of citrate vs. heparin, 1.37 [95% CI, 0.95–1.95); P = 0.088). Therefore, the type of anticoagulants may affect the infection rate—at least partly—indirectly via mean filter lifespan. Compared with heparin, citrate led to longer mean filter lifespan, and longer filter lifespan led to higher infection rate. Catheter-related infections were not the underlying cause of infections in this study. We compared patients with a mean filter lifespan of 48 hours or less (n = 362) to those with a mean filter lifespan of more than 48 hours (n = 213) with respect to all baseline characteristics reported in Table 1. There were no significant and/or relevant differences between patients. We performed sensitivity analyses to investigate if our result regarding the impact of mean filter lifespan rather than type of anticoagulation on new onset of infections is owing to confounding. Confounding by modality (CVVH/CVVHDF/CVVHD), hypophosphatemia, and CRRT dose were ruled out. In addition, our results cannot be explained by a different exposure to prophylactic systemic heparin in surgical compared with nonsurgical patients, as the exposure did not differ between the two groups.

Table 1. Baseline Characteristics

 All Patients (n = 596)No Infection (n = 228)Infection* (n = 368)
Demographics
 Age, mean (SD), yr67.5 (12.4)68.1 (11.3)67.2 (13.0)
 Weight, mean (SD), kg87.8 (25.0)89.8 (28.2)86.5 (22.8)
 Height, mean (SD), cm173.3 (8.9)173.9 (8.9)173.0 (8.9)
 Sex, n (%)
  Male413 (69.3)162 (71.1)251 (68.2)
  Female183 (30.7)66 (28.9)117 (31.8)
Baseline characteristics
 Baseline creatinine, mean (SD), mg/dl1.1 (0.4)1.1 (0.3)1.1 (0.4)
 eGFR, mean (SD), ml/min/1.73 m267.3 (24.2)67.5 (21.5)67.1 (25.7)
Comorbidities, n (%)
 Hypertension414 (69.8)161 (70.9)253 (69.1)
 Chronic kidney disease (eGFR < 60 ml/min/1.73 m2)248 (41.8)92 (40.7)156 (42.5)
 Congestive heart failure170 (30.9)70 (32.6)100 (29.8)
 Cardiac arrhythmia214 (36.0)74 (32.6)140 (38.0)
 Diabetes179 (30.0)66 (28.9)113 (30.7)
 COPD96 (16.1)39 (17.1)57 (15.5)
 Cirrhosis9 (1.5)4 (1.8)5 (1.4)
Source of hospital admission to ICU, n (%)
 Surgical453 (76.0)173 (75.9)280 (76.1)
 Non-surgical143 (24.0)55 (24.1)88 (23.9)
Reason for admission to ICU, n (%)
 Cardiac surgery155 (26.0)60 (26.3)95 (25.8)
 Sepsis109 (18.3)43 (18.9)66 (17.9)
 General Surgery74 (12.4)23 (10.1)51 (13.9)
 Vascular Surgery54 (9.1)23 (10.1)31 (8.4)
 Pneumonia/ARDS51 (8.6)21 (9.2)30 (8.2)
 Trauma29 (4.9)11 (4.8)18 (4.9)
 Other124 (20.8)47 (20.6)77 (20.9)
Clinical measures at randomization, n (%)
 Mechanical ventilation491 (82.4)181 (79.4)310 (84.2)
 Receiving vasopressors544 (91.6)205 (90.7)339 (92.1)
 Creatinine, mean (SD), mg/dl2.4 (1.1)2.5 (1.1)2.4 (1.1)
 Oliguria505 (84.7)192 (84.2)313 (85.1)
 SOFA score, mean (SD)11.5 (3.0)11.5 (3.1)11.5 (2.9)
 APACHE II, mean (SD)28.4 (7.0)28.6 (6.9)28.3 (7.1)
 Fluid balance, median (IQR), ml4393 (1496–8373)4310 (1536–8701)4396 (1449–7950)
Indication for CRRT, n/N patients with nonmissing data (%)
 KDIGO stage 3362/596 (60.7)141/228 (61.8)221/368 (60.1)
 Clinical indication521/596 (87.4)197/228 (86.4)324/368 (88.0)
 Urine output < 200 ml/12h or anuria210/345 (60.9)69/121 (57.0)141/224 (62.9)
 Fluid overload with edema163/338 (48.2)55/117 (47.0)108/221 (48.9)
 Serum urea > 150 mg/dl81/350 (23.1)27/121 (22.3)54/229 (23.6)
 Potassium > 6 mmol/l54/350 (15.4)24/121 (19.8)30/229 (13.1)
 Blood pH < 7.1522/349 (6.3)12/121 (9.9)10/228 (4.4)

Definition of abbreviations: APACHE = Acute Physiologic Assessment and Chronic Health Evaluation; ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease; CRRT = continuous renal replacement therapy; eGFR = estimated glomerular filtration rate; IQR = interquartile range; KDIGO = Kidney Disease Improving Global Outcomes; SOFA = Sequential Organ Failure Assessment.

*New culture-proven infection since start of dialysis.

These results appeared to be driven mainly by effects in nonsurgical patients. Those who received citrate had an increased infection rate compared with nonsurgical patients who received heparin (OR, 3.32 [95% CI, 1.64–6.71]; P = 0.001)., whereas in patients receiving surgery, we did not observe a difference in infection rate for citrate versus heparin (OR, 1.40 [95% CI, 0.96–2.05]; P = 0.085).

It is conceivable that there may be some changes in the filter profile and structure that may lead to a higher infection rate. The lack of differences in bacteremia makes the direct seeding of bacteria from the membrane unlikely. Increased inflammation leading to immune suppression is a possible explanation and will be the focus of future investigation.

Additional event-time analyses of new-onset infections confirmed that mean filter lifespan was associated with a significantly increased hazard of infection. In contrast to the rate of infections with adjustment for the mean filter lifespan, the type of anticoagulation still remained significant (regional citrate versus systemic heparin: hazard ratio, 1.28; P = 0.020). Citrate may lead to earlier onset, but over the whole duration of ICU stay not to more frequent new onset of infections than heparin.

This is a post hoc analysis of the RICH trial, and the study was not powered to detect significant differences in infection rates. However, we accounted for factors that may be associated with infections (preexisting comorbidities, illness severity, and renal replacement therapy) and found no effects of these variables on the development of new infections except filter lifespan, which underlines our conclusion.

In conclusion, we have shown that a longer mean filter lifespan was independently associated with an increased rate of new infection, and compared with 48 hours or less, the risk became significant after 48 hours. The type of anticoagulation did not appear to affect the infection rate directly. The increased infection rate associated with a longer filter lifespan might be related to a reduced filter efficacy over time, greater number of circuit sampling, or higher bacterial contamination of the circuit associated with a longer use of the system (4). However, the observation that a longer mean time on the same filter is associated with higher infection rate is novel. It clearly warrants further investigation as, if confirmed, it would have immediate implication for clinical practice.

The authors thank all the study nurses of all participating centers for data entry and the staff in the participating ICUs for their hard work.

1. Hoste EAJ, Kellum JA, Selby NM, Zarbock A, Palevsky PM, Bagshaw SM, et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol 2018;14:607625.
2. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 2015;41: 14111423.
3. Zarbock A, Küllmar M, Kindgen-Milles D, Wempe C, Gerss J, Brandenburger T, et al.; RICH Investigators and the Sepnet Trial Group. Effect of regional citrate anticoagulation vs systemic heparin anticoagulation during continuous kidney replacement therapy on dialysis filter life span and mortality among critically ill patients with acute kidney injury: a randomized clinical trial. JAMA 2020;324: 16291639.
4. Moore I, Bhat R, Hoenich NA, Kilner AJ, Prabhu M, Orr KE, et al. A microbiological survey of bicarbonate-based replacement circuits in continuous veno-venous hemofiltration. Crit Care Med 2009;37: 496500.
*Corresponding author (e-mail: ).

Supported by the German Research Foundation, Deutsche Forschungsgemeinschaft (ME5413/1-1 [to M.M.], ZA 428/10-1, ZA 428/21-1, and KFO 342/1). The study sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Author Contributions: Study concept and design: A.Z. and J.G. designed the analysis. Analysis and interpretation of data: A.Z., J.G., T.B., and J.A.K. Drafting of the manuscript: A.Z., J.A.K., J.G., and T.B. Critical revision of the manuscript for important intellectual content: J.G., M.M., D.K.-M., C.W., J.A.K., and A.Z. Statistical analysis: J.G. Obtained funding: A.Z. All authors read and approved the manuscript. A.Z., J.G., and M.M. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Originally Published in Press as DOI: 10.1164/rccm.202201-0063LE on May 13, 2022

Author disclosures are available with the text of this letter at www.atsjournals.org.

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