DO WE USE CONTINUOUS RENAL REPLACEMENT THERAPY FOR ACUTE KIDNEY INJURY IN SERBIA? – THE MULTICENTRIC SURVEY

Background / Aim. Absence of clear guidance in the definition, diagnostics and indications for renal replacement treatment (RRT) is present. The aim of this survey is creating a unique strategy for diagnostics and treatment of acute kidney injury (AKI) based on the current clinical practice. Methods. ? Results. We have conducted a multicentric web-survey among nephrologists (46.8%) and other physicians in Serbia. The sample consisted of 119 participants, 78.9% out of which filled out the survey forms correctly, and were, therefore, included in the analysis. Most of them responded that the nephrologist indicates (76.8%) and prescribes (74.5%) of continuous renal replacement therapy (CRRT).The application of KDIGO 2 criterion for „early” start of CRRT used 74.5% of the respondents, and 91.5% of them started „late” initiation of CRRT in the presence of complications associated with AKI or poor response to conservative treatment. Regarding clinical experience of the respondents, 74.5% of them marked „early” start of CRRT within 12 hours whereas 56.4% of them considered the start of CRRT after 48h as „late”. The most commonly used modality was continuous venous hemodiafiltration (37.6%). Most participants used heparin as anticoagulant (95.7%) with average life span of filters less than 24 hours (71.3%) and 25 ml/kg/h efficiency target dialysis effluent dose (45.2%) during CRRT. The most common complications of CRRT were hypotension (55.3%) and catheter-related infections (29.8%). Conclusion. „Early” start of CRRT is considered favorite by the majority of the participants. According to the obtained data, standardization of the strategy in the diagnostics and treatment of AKI is necessary.


Introduction
Acute kidney injury (AKI) has a particularly high incidence in admissions to the Intensive Care Unit (ICU), with reports of an incidence range from 16.0%-36.0% and a three-to five-fold increase of in-hospital mortality (compared to those without AKI). Despite the evolution of the guidelines for diagnosing AKI, we are still largely indebted to serum creatinine, as well as urinary output, to determine the stage of AKI. Thus, while the unification of criteria for AKI is useful for furthering clinical research, it still permits only a relatively late diagnosis. In any case, these biomarkers (as well as others undergoing clinical research) are still too innovative to clinical practice and in many low-and middle-income countries and lower resource areas of high-income countries are too expensive for widespread utilization. In general, outcomes for AKI are poor, with one systemic review of over 300 cohort studies revealing an overall mortality of 23.9% among adult AKI patients (1). With AKI not requiring dialysis and AKI requiring dialysis both rising, it remains unclear whether this is due to changes in International Classification of Diseases coding, changes in AKI definition, awareness of AKI, or clinical practice (2). As no specific pharmacological therapy is effective in AKI patients, their care is limited to supportive management in which continuous renal replacement therapy (CRRT) plays a central role (3).
Although there are many aspects of CRRT that are still under debate, its lifesaving potential in severe cases of AKI cannot be questioned (4).
The primary objective of this research is to help outlining future clinical work to improve the treatment outcome and reduce complications.

Methods
The questionnaire was distributed among physicians of different specialties.
Nephrologists, anesthetists, intensivists, cardiologists and internists mostly from tertiary and secondary health care institutions were invited to participate voluntarily and anonymously. The questionnaire was drawn up in accordance with the standard clinical practice (1). The 40-question survey form included 4 parts: 1) information on the type of specialty, type of institution and length of service of the physician 2) information on AKI definition and classification, indications and contraindications of CRRT, optimal start (regarding time, biomarkers, biochemical parameters) and termination of CRRT treatment 3) information on the choice of vascular approach, type of modality, dose administered, and anticoagulation, 4) information on complications of CRRT, renal function recovery, dialysis dependence, and mortality. All the data regarding statistical analysis were 6 compiled from hardcopy sources and processed by using a Microsoft Excel database/ datasheet. All the data are presented either as a percentage or as absolute numbers of the questionnaires.

Results
Out of the 119 survey participants, 78.9% fully completed the survey form. 21.0%-30% -18.1% and more than 30.0% -14.9% of the respondents). The majority of participants (74.5%) use the KDIGO 2 criterion when deciding on "early" CRRT initiation, and 91.5% start "late" CRRT for AKI complications (oliguria/anuria, elevated creatinine, hyperkalaemia, metabolic acidosis and/or refractory hypervolaemia) or a lower response to conservative therapy. In addition to the above criteria, regarding the clinical experience of the subjects, 46.8% thought that the "early" onset of CRRT should be within 6h (Figure 2), whereas 22.3% said that the "late" onset was > 24 hours, a similar percentage of respondents (21.3%) thought it was from 24-48 hours, and the majority (56.4%) thought the "late" onset of CRRT was 7 > 48 hours. The prediction for the onset of RRT could be increased by functional tests (Furosemide stress test), considered relevant by most of the participants (63.8%). Regarding the use of biomarkers as predictors of onset of RRT, 43.6% of these indicated cystatin C in urine, 36.2% referred to Neutrophil gelatinase-associated lipocalin in urine and 20.3% indicated a combination of urine tissue inhibitor of metalloproteinase 2 (TIMP-2 ) and insulin-like growth factor (IGF) binding protein 7, whereas 3.2% were related to other biomarkers ( Figure 3). As high as 77.7% stated that the severity and course of the disease were the determining factors for initiation of RRT, but that the decision was also influenced by the availability  (Table 1).

Discussion
The lack of clear guidelines in the definition, diagnosis and treatment of AKI, as well as the fact that standard biochemical and clinical parameters as well as new biomarkers did not optimize treatment outcomes, indicates the need for further research. The main objective of this multicentric research is to summarize CRRT clinical practice information for one year in order to gain insight into the most important issues, especially treatment timing and to guide clinicians in their daily work. Our subjects use almost equally high (≥250 mg/day) and low doses of Furosemide (≤250 mg/day) in the conservative treatment of AKI, and a relatively equal representation in the range of up to 30.0% of AKI patients requiring CRRT is reported. These results are different from last year's study in which it was stated that most use high doses in oligurian patients and that 13.0% of patients require CRRT (5). In our institutions, most respondents stated that they use the KDIGO 2 criterion for "early" start of CRRT, and for already present complications associated with AKI or poor response to conservative therapy, participants start CRRT "late". Compared to comprehensive clinical work so far, almost 50.0% believe that the timeline for "early" start of CRRT should be within 12 hours, which corresponds to the KDIGO 2 criterion, and slightly more than 50.0% believe that over 48 hours is "late" start. These early start CRRT results rule out urgent indications and leave time for patient monitoring and clinical evaluation for late start. However, Thakar VC and colleagues reported in their survey that 53.0% of respondents felt that there was no benefit from early-start CRRT, moreover 35.0% of respondents believed that the risk of early CRRT outweighed the benefit. However, 46.0% of respondents indicated that they often initiate "early" CRRT in patients with AKI in ICU. Most influential parameters in determining dialysis initiation were complications of AKI, such as hyperkalemia and hypoxemia due to volume overload, whereas the degree of severity of kidney injury or markers of azotemia played a less important role in the early dialysis decision (8). In their work, Clark and associates have shown that potassium levels and pulmonary edema are the most common indicators of early CRRT (9). The aforementioned surveys were conducted in 2012, when different biochemical and clinical parameters were used in deciding to initiate CRRT. By defining the KDIGO guidelines in the same year in the AKI classification, the use of the same was made possible in the following years, and the above mentioned surveys are not comparable with ours. Most believe that the Furosemide Stress Test, Cystatin C, and NGAL in the urine could increase the prediction for the start of CRRT. Our centers have no experience in using biomarkers other than Cystatin C, and this may be the reason why only 20.3% of respondents said that (TIMP-2)•(IGFBP7) and other biomarkers would be good predictors. In a previous survey, 60.0% of participants indicated that they were implementing new biomarkers in their practice and research (9). It is interesting to note that 77.7% still consider the severity and course of the disease to be the deciding factors for the start of CRRT, which indicates the importance of the "clinical scenario" as the most important part of the strategy in the treatment of AKI and also meets the current "watchful waiting" recommendations. However, the responses of the rest of the participants stating comorbidities, response to diuretic therapy, and availability (appliances, equipment, staff), day of the week, and time of day   11 are not negligible. It should be noted that none of the subjects indicated a decisive factor for the start of CRRT, but 4.3% indicated that older age was a relative contraindication for start of CRRT. Just over 50.0% of participants except in the use of anticoagulation (mostly unfractionated heparin followed by citrate, low molecular weight heparin, and regional anticoagulant therapy) (5). Overberger and associates stated that in their study CRRT was also the most commonly used modality of therapy as well as the applied dialysis effluent dose of 25 ml/kg/h (10). In another earlier study, over 90.0% of subjects used CRRT, however, the most commonly prescribed dose was 35 mL/kg/h (8). In our study, adsorptive membranes are used by 60.6% of subjects to treat sepsis in AKI (Emic-2-50.6% were the most prevalent).
The most common complications of CRRT are hypotension 55.3% followed by catheter-related infection with an incidence of 1-6/1000 catheter days reported by most subjects similar to the results of certain previous studies (11)(12)(13). In our patients who required CRRT, the majority of respondents stated that up to 20.0% of patients had renal function recovery by 3 months, and that in the same percentage some patients have some stage of chronic renal failure/dialysis dependency/death in the first year. Those that survive the initially high mortality rate associated with dialysis-requiring AKI, mostly become independent of renal replacement therapy (RRT) within a year, but some of them do go on to develop chronic kidney disease and even progress to end-stage renal disease (14).
It is unclear whether a preventive/early strategy of the initiation of RRT in order to avoid complications associated with AKI leads to better patient outcomes and the use of health services, or a more conservative strategy in which RRT is started as a response to the development of complications provides better results (15). About 50.0% of the respondents stated that least patients died with "early" start of RRT, as opposed to the "late" start of RRT, which was confirmed in our single-center retrospective study of 385 patients with acute kidney injury who were admitted between 2014 and 2017 (16).

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About half of the physicians reported that patients with late dialysis start had the recovery of renal function in the lowest number, while one in three respondents said that 20.0%-40.0% of patients who started dialysis "early" recovered the renal function. Recent meta-analyzes are also remarkably clear, noting that increased mortality and recovery of renal function by early dialysis stems from lower quality data (i.e., high heterogeneity and / or higher risk of bias). Meanwhile, an analysis of high-quality pooled data shows no significant difference in mortality (17)(18)(19)(20)(21)(22).  Outcomes AKI required RRT patients (Early vs Late start RRT)