Cheng Hang, Li-jun Liu, Zhao-yun Huang, Jian-liang Zhu, Bao-chun Zhou, Xiao-zhen Li

1 Intensive Care Unit, Kunshan Hospital of TCM, Suzhou 215300, China

2 Intensive Care Unit, the Second Affi liated Hospital of Soochow University, Suzhou 215004, China

KEYWORDS: Acute kidney injury; Continuous renal replacement therapy; Solute removal effi ciency; Delivered dose

INTRODUCTION

Acute kidney injury (AKI) is a syndrome characterized by a rapid (hours to days) deterioration of kidney function.The incidence of AKI among critically ill patients and ST-segment elevation myocardial infarction (STEMI) patients is approximately 34% and 10%, respectively.AKI is an independent risk factor for the prognosis of critical illness and causes high mortality of 62%.Meanwhile, an epidemiological study in China indicated that approximately 1.4–2.9 million AKI patients were annually admitted; out of these patients, 28.5% were admitted to ICUs, and about 11.8% required renal replacement therapy.Despite being expensive, continuous renal replacement therapy (CRRT)is currently the most prevalent renal replacement therapy used in the ICU.A survey conducted in Jiangsu Province revealed that the average medical cost of CRRT for one AKI patient was 19,525 yuan.The cost of AKI treatment poses a signif icant burden to society and families. Thus, it is important to balance the treatment effi cacy and its cost.

In the current clinical practice, CRRT filters are regularly replaced based on the manufacturer’s instructions. Meanwhile, an unscheduled replacement can happen for various reasons, such as instances of filter clotting and catheter malfunction.Several studies indicate that the delivered dose of CRRT gradually decreases as the permeability of the filter membrane decreases with the extension of treatment time.Nonetheless, whether filter replacement based on schedule affects patient outcomes remains to be further investigated. Besides, it is essential to identify appropriate indicators for f ilter replacement.

Therefore, in this single-centered, randomized, and crossover trial, we analyzed dynamic changes of serum levels of solutes and relevant indicators of the two most common CRRT modalities, i.e., continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodiafiltration (CVVHDF), in order to identify an optimal indicator for changing the filter of CRRT thus improving treatment effi ciency.

METHODS

Baseline characteristics

AKI patients requiring CRRT treatment in an ICU in the Second Affi liated Hospital of Soochow University between July 2017 and December 2018 were recruited.

Inclusion criteria included: (1) nonsurgical patients,age ≥18 years old; (2) AKI diagnosed based on the KDIGO clinical practice guidelines for acute kidney injury, 2012;(3) AKI patients with indicators that initiated CRRT, i.e., (a) stage 2 of AKI (supplementary Tables 1 and 2); (b) AKI patients combined with acute hypervolemic heart failure, acute pulmonary edema,hemodynamic instability due to septic shock,severe acid-base and electrolyte disorders, multiple organ dysfunction that necessitated CRRT.

Exclusion criteria included: (1) patients with chronic renal failure or end-stage renal disease receiving maintenance dialysis; (2) the required treatment parameters could not be used because of the disease condition; (3) during the treatment process, the treatment mode and parameters needed to be changed according to the disease condition; (4) during the treatment process, the patient condition significantly changed,hence unsuitable to continue in the clinical trial; (5) the crossover remained unf inished because of the withdrawal or death.

Study design

Using a crossover design,the recruited AKI patients were randomly divided into groups A and B using random numbers and envelope methods. Patients in the group A firstly received CVVH followed by CVVHDF. Conversely, patients in group B firstly received CVVHDF followed by CVVH. Since CRRT treatment did not have an apparent carry-over eff ect, nontreatment time for 30–40 minutes was required to switch from CVVH to CVVHDF and vice versa, which could be a suffi cient wash-out period of the previous treatment.

CRRT parameters

Femoral vein catheterization was performed in all patients. The prescribed dose of both CVVH and CVVHDF was 35 mL/(kg?h) (post-dilution). The rate of dialysate flow and replacement fluid flow of CVVHDF was 1:1. The f ilter and circuit were pre-washed using 3 L normal saline with 37,500 U heparin sodium, maintained at 3–5 U/(kg?h) in the process of CRRT. The activated partial thromboplastin time (APTT) of the filtered blood was maintained at 1.5–2.0 times of normal level by adjusting the dose of heparin. Filter replacement indicators were: transmembrane pressure (P) increase(≥300 mmHg [1 mmHg=0.133 kPa]), and pre-filter pressure (P) increase (≥300 mmHg), f ilter and circuit use time reaching the specif ied length (≥60 h).

Observational indices

Observational indices included: (1) clinical characteristics: Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, serum level of urea nitrogen, creatinine, β-microglobulin, and cystatin C before treatment; (2) solute removal effi ciency: delivered dose (specif ic serum solute delivered clearance calculated using it’s measured blood and effluent concentration),serum solute concentration, Pand Pat diff erent time points; (3) patient outcomes: duration of mechanical ventilation, length of ICU stay, renal function recovery rate, and the in-hospital mortality rate.

Sample collection and analysis

Blood samples were collected every 12 h after CRRT treatment initiation (the f irst sample was delayed 30 min to avoid pre-wash fluid contamination). Pand Pat the time of collecting blood samples were recorded. Urea nitrogen, creatinine, β-microglobulin, and cystatin C in blood and effl uent samples were detected for calculating the delivered doses. The detailed equipment and materials were listed in the supplementary Table 3.

Formulas of calculating prescribed doseand delivered dosewere as follows:

(1) Prescribed dose (, mL/[kg?h])

The above formula was used for the calculation of the delivered dose of urea nitrogen. Solutes with other molecular weights were similarly calculated. In this formula,was the dialysate f low rate (mL/h),was the ultraf iltration rate (mL/h),was the body weight of the patient (kg),was the replacement liquid f low rate(mL/h),was the net ultraf iltration rate (mL/h),was the urea nitrogen level in the ultraf iltration,was the urea nitrogen level in the blood (mmol/L), andwas the effl uent f low rate (mL/h).

Statistical analysis

The SPSS 23.0 software was used for statistical analyses. Enumeration data were expressed as number(%) and compared using thetest. Fisher’s exact test was performed in the condition where total frequency<40 or the frequency <1. Normally distributed measurement data were expressed as mean±standard deviation and compared using the single factor-test;otherwise, they were expressed as median (interquartile range), and independent and paired samples were compared using Mann-Whitney-test and Wilcoxon signed-rank test, respectively. Partial correlation analysis was performed to identify a correlation between delivered dose and Pand P. Receiver operating characteristic (ROC) curves were generated to assess the sensitivity and specificity of Pin predicting the time to change the filter. A-value <0.05 was considered statistically signif icant.

RESULTS

Baseline characteristics of recruited AKI patients

A total of 90 critically ill patients were recruited,whereas 26 were excluded. In total, 64 cases were randomly divided into groups A and B. During the treatment, 12 cases gave up the treatment, and 2 cases altered treatment parameters. Consequently, clinical data of 14 cases were not analyzed. Eventually, 50 eligible cases were analyzed, 27 cases in the group A and 23 in the group B. Flow chart showing the recruitment and research method is illustrated in the supplementary Figure 1. No significant diff erences were noted in sex, age, APACHE II score, SOFA score, serum urea nitrogen, creatinine, β-microglobulin, and cystatin C between groups (all>0.05). There were also no significant differences in patients’ duration of mechanical ventilation, length of ICU stay, renal function recovery rate,and in-hospital mortality rate between groups (all>0.05)(Table 1).

Dynamic changes of delivered doses

With the prolongation of CRRT, the delivered doses of small- and medium-molecular-weight solutes were decreased when treatment ceased (filter and circuit replacement),compared with delivered doses at the initiation of CRRT treatment, particularly those of medium-molecular-weight solutes (supplementary Figure 2).

In CVVH mode, delivered doses of urea nitrogen,creatinine, β-microglobulin, and cystatin C decreased by 2.3% (0.4%–4.0%), 1.9% (0.2%–4.2%), 44.1% (15.8%–62.6%), and 45.5% (22.5%–70.3%), respectively (all<0.05).

In CVVHDF mode, the delivered doses of urea nitrogen,creatinine, β-microglobulin, and cystatin C decreased by 3.5% (0.5%–5.1%), 2.5% (0.5%–6.2%), 41.5% (16.9%–54.8%), and 45.1% (1.8%–68.4%), respectively (all<0.05).

Dynamic changes of serum solute levels

Serum levels of small-molecular-weight solutes gradually decreased during the whole process of CRRT,whilst those of medium-molecular-weight solutes sharply decreased in the early stage of the treatment, then the magnitude of the decrease smoothly reduced in the middle and late stages. Moreover, the rebound of serum mediummolecular-weight solutes was observed in most patients in the late stage of CRRT treatment, which was more frequently observed with the prolongation of CRRT in both CVVH and CVVHDF mode. However, no significant difference between the two modalities was detected (>0.05) (Table 2).

Correlation analysis between delivered dose and PPRE and PTM

No significant correlation was noted between Pand delivered dose of either small-molecular-weight solutes or medium-molecular-weight solutes (both>0.05). Pwas significantly correlated with the delivered dose of medium-molecular-weight solutes, rather than that of smallmolecular-weight solutes (<0.05). In CVVH mode, Pwas negatively correlated with the delivered dose of β-microglobulin (= –0.458,<0.01) and cystatin C (=–0.226,<0.01). In CVVHDF mode, Pwas negatively correlated with the delivered dose of β-microglobulin(= –0.503,<0.01) and cystatin C (= –0.296,<0.01)(supplementary Figure 3).

Potential of PTM in predicting the time to change the f ilter

The time point when a rebound of serum solutes occurred was considered the optimal time to change the filter of CRRT. As stated above, Pwas negatively correlated with delivered doses. To further investigate the predictive potential of P, ROC curves were generated to assess the sensitivity and specificity of Pin predicting the rebound of β-microglobulin and cystatin C.

The area under the curve (AUC) of Pin predicting the rebound of β-microglobulin was 0.651 (<0.01), and the threshold of Pwas 146.5 mmHg (sensitivity=0.479,specif icity=0.811) (Figure 1A).

The AUC of Pin predicting the rebound of cystatin C was 0.717 (<0.01), while the threshold of Pwas 146.5 mmHg (sensitivity=0.512, specif icity=0.871) (Figure 1B).

DISCUSSION

In this study, we found that delivered doses of solutes with diff erent molecular weight decreased in both modalities of CRRT when treatment ceased (filter and circuit replacement), compared with delivered doses at the initiation of CRRT treatment. Nonetheless, during all the CRRT courses, we did not detect a rebound of serum concentration of small-molecular-weight solutes. The delivered doses of medium-molecular-weight solutes decreased far more significantly than those of smallmolecular-weight solutes; as a consequence, a rebound in their serum concentration was noted in most patients.

During CRRT treatment, clinicians and nurses often maximize the filter life span to minimize the treatment cost. Nevertheless, prolonged f ilter use causes membrane rupture, hence harming the patient. Thus,filters are often regularly replaced in the absence of clotting as per the experience or manufacturer’s safe use time limits. A recent study reported that the use of citrate anticoagulation and non-convective modalities in reducing hemoconcentration prolonged the use of f ilters,thereby minimizing the treatment cost.Nonetheless,our study and several othersindicate that thedelivered dose of CRRT gradually decreases as the f ilter membrane permeability decreases with the extension of treatment time. As such, the f ilter should be replaced before the delivered dose decreases. However, how often the filter should be replaced remains unresolved.Regarding the economics of treatment, a few studies minimized the cost of treatment by reducing the amount of replacement fluidor using cheaper replacement f luid.Here, we consider that instead of sacrif icing the treatment dose of patients or even treatment safety to reduce costs, it is sustainably economical to f lexibly use f ilters according to the treatment eff ect on patients. Thus,based on our f indings, for patients requiring the removal of small-molecular-weight solutes, the filter should be used as long as possible within the manufacturer’s safety limits. This lowers the treatment costs and increases treatment efficiency since the serum concentration of small-molecule-weight solutes continuously decreases during the treatment course. On the other hand, for patients requiring removal of medium-molecular-weight solutes, the filter should be replaced when the efficacy of the filter decreases to the point where it is unable to regulate the serum concentration of medium-molecularweight solutes, and it’s the point where patients’ serum medium-molecular-weight solutes concentration rebounded. This occurs in the second half of the treatment; at this point, the treatment should ideally be stopped because the serum solute concentration of the patients cannot be effectively regulated due to filter function impairment.

Table 1. Clinical data of AKI patients before treatment

Table 2. Rebound ratio of serum solutes

Our study confirmed that Pwas significantly and negatively correlated with the delivered dose of medium-molecular-weight solutes in diff erent treatment modalities; i.e., an increase in Pindicated a decrease in the delivered dose. ROC curves demonstrated that Pcould precisely predict the rebound of serum level of cystatin C. Notably, the production rate of serum cystatin C is relatively constant, while that of β-microglobulin is affected by multiple factors.Thus, cystatin C is a promising indicator for serum levels of solutes. When Preaches 146.5 mmHg, the delivered dose of mediummolecular-weight solutes may be insuffi cient to regulate serum levels of solutes. Therefore, the time at which Preaches 146.5 mmHg may be the optimum time to change the f ilter among patients requiring the removal of medium-molecular-weight solutes.

Noteworthily, an important feature of ICU patients is their heterogeneity. For instance, the primary diseases were not identical. Besides, the treatment for their primary diseases was inconsistent or individualized even with the adoption of similar CRRT treatment parameters and modalities. In addition, pathophysiologic conditions including renal functional status are constantly changing in diff erent patients, and the response to treatment varies in different stages of the disease. These potentially trigger variability in test results, specifically in small sample sizes.A crossover experimental design was used to markedly eliminate the effect of differences in the underlying characteristics of diff erent patients on the experimental results.

Figure 1. ROC curves depicted for PTM. A: predicting the rebound of serum level of β2-microglobulin; B: predicting the rebound of serum level of cystatin C.ROC: receiver operating characteristic; PTM: transmembrane pressure.

This study has some limitations. First, it is a singlecenter study with a relatively small sample size (=50).Although a crossover design was adopted, there was a possibility of errors due to the small sample size. In addition, numerous treatment and monitoring parameters of CRRT have been reported, and whether additional reliable indicators of filter replacement are available remains to be investigated.

CONCLUSIONS

In summary, the filter can be used during CRRT as long as possible within the manufacturer’s safe use time limits to therapeutically remove small-molecular-weight solutes. Meanwhile, Pof 146.5 mmHg may be an optimal indicator for changing the filter when removing mediummolecular-weight solutes during CRRT.

The study was supported by Kunshan Science and Technology Special Fund (Social Development Category,KS18040).

This trial protocol was reviewed and approved by the ethics committee of the Second Affiliated Hospital of Soochow University.

The authors declare that there is no conf lict of interest.

CH designed the research and wrote the paper. All authors contributed to the design and interpretation of the study and to further drafts.

All the supplementary files in this paper are available at http://wjem.com.cn.