Renal Replacement Therapy for Burn Patients: A Systematic Review and Meta-Analysis

Background: To improve the prognosis of burn patients with renal replacement therapy (RRT), we performed this systematic review and meta-analysis. Methods: We searched multiple databases for studies published before February 2020. Studies about adult populations with burn injury, providing epidemiologic data on prevalence or mortality of RRT, were included. Results: A total of selected 58 studies, including 38,787 patients were enrolled in our analysis. The prevalence rates of RRT were 5.14% (95%CI 4.54%-5.74%) in all burn patients and 35.8% (95%CI 29.54%-42.07%) in acute kidney injury (AKI) patients. The prevalence of RRT among burn patients in the intensive care unit (ICU) was 10.92% (95%CI 8.71%-13.14%). The mortality of all burn patients with RRT was 65.52% (95%CI 58.41%-72.64%). The mortality of patients with RRT in ICU was 62.7% (95%CI 53.7%-71.7%). The mortality rate of RRT patients was 30.33% (95%CI 22.06%-38.59%) of the total. There was no signicant correlation (r=-0.224, P=0.159) between the year of publication and the mortality of burn patients with RRT. Neither cohort studies nor RCT studies of subgroup analyses show that RRT could reduce the risk of death in burn patients with AKI. Bleeding (10.92%) and secondary infection (9.61%) were the most common RRT-related adverse reactions. Compared with heparin, regional citrate anticoagulation has advantages in superior lter life spans and fewer bleeding episodes. Dialysis-requiring AKI in burn patients could increases the risk of chronic kidney disease progression and end-stage renal disease. About 35% of RRT patients need to maintain hemodialysis temporarily, even if they survive and leave hospital. Conclusions: The prevalence of RRT is not low; approximately, one-third of burn patients with AKI need RRT. The mortality of burn patients with RRT is very high and accounts for 1/3 of the total deaths. There is no evidence that RRT can improve the prognosis of burn patients with AKI. Regional citrate anticoagulation has some advantages in reducing bleeding and extending lter life spans, which suitable for severe burn patients with CRRT. a multicentre, prospective, randomized, controlled clinical trial to evaluate the impact of high-volume haemoltration (HVHF) on the haemodynamic prole of burn patients with septic shock and AKI. They concluded that HVHF was effective in reversing shock and improving organ function in burn patients with septic shock and AKI, but the data were insucient to comment on improving survival (9). Another random prospective study concluded that HVHF conducted in the early stage (within 3 days) could the incidence of sepsis and the mortality of patients with severe burns Yoon 2017-burns found that early or late continuous renal replacement therapy (CRRT) did not change the prognosis of burn patients with AKI. In their multivariate logistic regression analysis, only sepsis had an independent association with mortality of the existing single-centre, small-sample, retrospective or involved the examination of a single or a few variables. the ndings on RRT for burn patients varied or improve the prognosis of burn patients with RRT, we selected eligible studies related to RRT in burn A recent study found an odds of dialysis of 2.40 in burn patients who developed AKI compared with the general Finnish population (71). Eleven studies followed up the long-term renal outcomes of burn patients who survived RRT (9, 18, 19, 21, 27, 30, 34, 36, 37, 50, 54). A total of 184 patients survived after renal replacement therapy; 64.13% of them (118/184) were dialysis-independent after discharge, 25% (46/184) needed temporary required dialysis, and 10.87% (20/184) needed long-term dialysis (more than 6 months after discharge). Thalji 2017 found that one year after burn, the proportion of chronic dialysis in non-AKI patients was 0.33% (56/16985), signicantly lower than that in patients with AKI, which was 4.58% (26/568) (72). The proportion of severe CKD (dened as stage 3–5 CKD) in non-AKI patients (0.71%) was also lower than those in AKI patients (5.81%) (72). Gille reported that 3 of the 16 surviving burn patients undergoing CRRT had CKD progression (GFR < 45 ml/min.1.73 m 2 , CKD 3b) (18.75%) (21). Two patients had slightly impaired GFR (< 90 ml/min.1.73 m 2 , CKD 2) before the burn trauma. One patient had normal GFR (21). function, renal replacement therapy was one of the standard treatment methods. In the principle of treatment, RRT can maintain the stability of the internal environment by controlling capacity overload, reducing organ damage, clearing inammatory mediators, and correcting electrolyte and acid-base balance disorders to benet AKI patients. At present, only a few retrospective match historical cohort studies had found that CRRT had better prognosis than conventional non-RRT therapy (44, 78). However, in a meta-analysis of the cohort studies included, we did not nd that RRT could reduce mortality. Compared with AKI or ARF, the risk of death in RRT patients was not signicantly reduced. A meta-analysis of three RCT studies also did not show that CRRT could reduce the risk of death in burn patients with AKI compared with the standard care. You 2018 found that administration of HVHF within 3 days after admission may reduce the 90-day mortality of patients with large-area severe burns ( ≥ 80% TBSA) (P = 0.049). This RCT study excluded burn patients with sepsis or multiple organ failure on admission (10). Early (0–3 days after injury) burn AKI is typically due to hypovolemia, poor renal perfusion, direct cardiac suppression from TNF-alpha, and precipitation of denatured proteins (79). The therapeutic effect of renal replacement therapy in the above aetiology is better. However, late AKI is often due to sepsis, multi-organ failure, and nephrotoxic drugs (79). Thus far, it is often believed that AKI related to these aetiologies cannot reduce mortality and improve the prognosis of patients. The beginning time of CRRT was different in Liu 2016 and only lasted until 72 hours after the injury. The results showed that CRRT could not improve the of metabolic acidosis in the citric acid group was slightly higher, but the not statistically signicant. the side effects of RRT, the results of this suggest that bleeding is the most common incidence of RRT in patients, an incidence of approximately 11%. The advantage of citric acid in reducing may be more for burn patients with AKI. Moreover, there is new evidence that RCA can safely be used in patients with liver failure (84, 85) and after liver transplant (86), suggesting that local citrate anticoagulation may also be used in severe burn patients with MOF combined with renal and liver failure. Other common adverse effects of RRT include secondary infection, electrolyte disorder, thromboembolism, disequilibrium syndrome and thrombocytopenia. Compared with haemodialysis, peritoneal dialysis has some advantages in bleeding, but its risk of secondary infection is also higher. Moreover, the peritoneal dialysis catheter placement area is a common donor site or burned area This limits the use of peritoneal dialysis in burn patients.


Introduction:
Acute kidney injury (AKI) is one of the common complications of burn patients that seriously threatens the life of patients and increases the length of stay, intensive care unit (ICU) length of stay and treatment costs (1,2). In 2010, meta-analysis reported that the prevalence of AKI in burn patients ranged from 16-26.6% (3), depending on the severity of the burns and on the de nition of AKI. The prevalence of AKI in burn patients ranged from 18.4-47.4% with the RIFLE standard (2). Burn patients with AKI had a signi cantly increased risk of death. The mortality of burn patients with AKI was 16.95-100%, signi cantly higher than that of their control group (7%-29.41%) (4-7).
However, the prevalence and mortality of renal replacement therapy (RRT) for burn patients are still unclear. A meta-analysis in 2010 conducted a subgroup analysis of the prevalence and mortality of RRT in burn AKI patients. The results showed that the prevalence of RRT was 3.2% in all burn patients and 27.1% in burn patients with AKI. The mortality of burn patients with RRT was as high as 80% (95%CI 72-88.6%) (3). However, the updated meta-analysis of burn patients admitted to the ICU showed that the prevalence of RRT in all burn patients was 12%, and the mortality was 74% (95%CI 58-87%) (8). The mortality of burn patients with RRT was very high. However, due to the different directions of attention, the literature of RRT for burn patients included in these studies is incomplete. At present, there is a lack of meta-analysis of RRT for burn patients. Moreover, to reduce the mortality of severe burn patients with AKI after 2010, many researchers have made many attempts for different dialysis modalities (continuous or intermittent), different treatment doses (high-volume or standard) and different anticoagulant methods (regional citrate anticoagulation vs heparin). Chung 2017 conducted a multicentre, prospective, randomized, controlled clinical trial to evaluate the impact of high-volume haemo ltration (HVHF) on the haemodynamic pro le of burn patients with septic shock and AKI. They concluded that HVHF was effective in reversing shock and improving organ function in burn patients with septic shock and AKI, but the data were insu cient to comment on improving survival (9). Another random prospective study concluded that HVHF conducted in the early stage (within 3 days) could reduce the incidence of sepsis and the mortality of patients with severe burns (10). Yoon 2017-burns found that early or late continuous renal replacement therapy (CRRT) did not change the prognosis of burn patients with AKI. In their multivariate logistic regression analysis, only sepsis had an independent association with mortality (11). Most of the existing studies are single-centre, small-sample, retrospective or involved the examination of a single or a few variables. Moreover, the ndings on RRT for burn patients were varied or contradictory. To improve the prognosis of burn patients with RRT, we selected eligible studies related to RRT in burn Search strategy We used the following terms for standard medical subject headings and free-text words: burn, burns, renal, kidney, kidney injury, kidney diseases, renal insu ciency, renal failure, and kidney failure. We also reviewed the references cited in all of the studies selected for review. An extensive search of literature published until January 2020 was conducted using the databases PubMed/MEDLINE, Embase, Science Citation Index (Web of Science), and the Cochrane Central Register of Controlled Trials (CENTRAL) database. Two searchers (D.ZY. and C.FK.) conducted the search independently. If one of the searchers thought that the article was appropriate, the study was selected.

Study selection
Two reviews (D.ZY. and C.FK.) independently screened studies for eligibility according to study selection criteria. The inclusion criteria were RCT, case-control and cohort studies. Cross-sectional studies were excluded because they cannot clearly identify the causal relationship between observed indicators and diseases. Only articles in English, Japanese or Chinese were included. Populations with paediatric patients, animal studies, case reports and reviews were excluded. Any disagreement between reviewers were resolved by consensus. RRTs included slow low-e ciency dialysis (SLED), IHD, PD and CRRT. If the patients used CRRT during hospitalization, we still classi ed them into the CRRT group even if other dialysis methods were also used. If the patient used peritoneal dialysis during hospitalization, even if other dialysis methods were used, we still classi ed them into the peritoneal dialysis group. We excluded the study of plasma exchange in burn patients because the mechanism and mode of treatment of plasma exchange are different from those of dialysis. We excluded the lack of mortality studies aimed at studying antibiotic pharmacokinetics in burn patients with RRT. For studies that gave multiple mortalities, we took the longest mortality, such as 28, 60, 90, or in-hospital mortality.

Study quality
We assessed risk of bias for RCTs using the Cochrane Collaboration's tool for assessing bias (14). We assessed risk of bias for casecontrol and cohort studies using the Newcastle-Ottawa Scale (NOS) (15). The NOS allocates nine points for quality of the selection (four items, four points), comparability (one item, two points), and outcome or exposure (three items, three points). Publication bias was assessed by creating and examining funnel plots. The robustness of the results was evaluated using sensitivity analyses. Each study included in this review was assessed for quality as good (7)(8)(9), moderate (4-6), or poor (≤ 3) based on scores.

Data extraction and statistical analysis
Two independent reviewers (D.ZY. and C.FK.) extracted the following information from the included studies: title, author, year, journal, study design, nationality, sample size, de nition of AKI, number of patients with or without AKI, number of patients with or without RRT, RRT details (modalities, device and manufacturer, dose, anticoagulants), and results (mortality of AKI patients, mortality of RRT patients). We also reported other outcomes (RRT complications, renal outcome-long-term dialysis, temporarily required dialysis, CKD progress).
All ambiguities in data extraction were double-checked and resolved. Relative risks (RRs) and 95% con dence intervals were obtained using a random effects model. I 2 derived from the chi-squared test was used to evaluate the heterogeneity across the included studies. An I 2 less than 50% indicated that there was no signi cant heterogeneity (16). Sensitivity analysis was performed by sequentially removing each individual study. We assessed publication bias by constructing a funnel plot. Pearson or Spearman's correlation was used to analyse correlations. A two-tailed P value of < 0.05 was considered statistically signi cant. All statistical analyses were performed using Review Manager version 5.3, R 3.5.1, SPSS 24.0 and R 3.5.1 software were used for meta-analyses of prevalence and mortality.

Results:
Quality assessment and study characteristics We screened and evaluated 4720 studies, assessing 194 for eligibility. The selected 58 studies, including 38,787 patients, were enrolled in our analysis ( Fig. 1) (1, 4-7, 9-11, 17-65). There were 4718 burn patients with AKI and 1764 burn patients with RRT. A total of 93.53% of the burn patients with RRT were AKI patients. Figure 1 shows a ow chart of the identi cation and selection of the studies.
Three RCT studies compared the effects of standard care (non-RRT) and CRRT on patients' prognosis (10,51,52). Two RCT studies did not nd that CRRT had a positive effect on the mortality of burn patients (51,52). You 2018 (10) found that early HVHF treatment may reduce 90-day mortality of patients with severe burns (≥ 80% TBSA) (P = 0.049). A meta-analysis of these three RCT studies also did not show that CRRT could reduce the risk of death in burn patients with AKI compared with the standard care (non-RRT) (RR = 0.64, 95%CI 0.40-1.03, P = 0.06; Fig. 3).

Regional Citrate Anticoagulation
Four articles reported the studies of regional citrate anticoagulation (RCA) for CRRT in burn patients, including 3 retrospective cohort studies (21, 55, 69) and 1 RCT study (70). The cohort studies found that the lter survival time (CRRT) of the citrate group was signi cantly longer than that of the heparin group (average 28.5-28.7 h vs 19-19.4 h) (55,69). When the dialysis mode was SLED, the lter survival time of the citrate group was still better than that of the heparin group (average 8-13 h vs 6.5-7 h) (55,70). Moreover, the citric acid group also had some advantages in the recovery time of urine volume and the length of stay in ICU (69). After 24 h of treatment, the coagulation index (PT and APTT) and the in ammation index (PCT and CRP) of the citric acid group were signi cantly lower than those of the heparin group (69). However, there was no signi cant difference in the risk of death between the two groups (P = 0.51, Additional le 1: Fig. S4). Only a small-sample RCT study was conducted to compare the effects of local heparin anticoagulation and local citrate anticoagulation for SLED-HF in severe burn patients (TBSA greater than 50%) with sepsis (70). The results also showed that the citric acid group had signi cant advantages in single treatment time, treatment time reaching rate (12 h), coagulation index (PT and APTT), and in ammation index (PCT and CRP) (70). All these literatures suggest that the incidence of bleeding events in the heparin group was signi cantly higher than that in the citric acid group (55,69,70). The incidence of hypocalcaemia in the citric acid group was 7.27% (4/55). The incidence rates of metabolic acidosis and metabolic alkalosis in the citric acid group were slightly higher than those in the heparin group, but the differences were not statistically signi cant (69).

RRT-related adverse reactions
Nine articles reported the incidence of RRT-related adverse reactions. The total incidence was 28.77% (63/229) ( reported in 9 articles; most of these patients were from Liu 1986 (28). Among the 16 patients, 1 had "unbalanced syndrome" and improved after stopping dialysis; 4 had abdominal infection, 3 survived, and 1 changed to haemodialysis and ultimately died. Considering the immature technology at that time, the incidence of PD adverse reactions may be overestimated.

Discussion:
Acute renal injury is one of the common complications in burn patients. The incidence of AKI varied from 16-26.6% according to the de nition of AKI in different populations (3). The incidence of AKI in burn ICUs was 38% (30-46%) (8). Renal replacement therapy was often needed by some severe burn patients with AKI. According to the subgroup analysis in the previous meta-analysis of burn patients with AKI, the proportion of all burn patients requiring RRT was approximately 3% (3). The proportion of burn patients admitted to the ICU was 12% (8-16%) (8), and the proportion of burn patients with AKI who needed RRT was as high as 30% (3). Moreover, the mortality of RRT in burn patients was as high as 80% (3). Such high mortality rates were the reasons we wanted to conduct a meta-analysis of RRT in burn patients. RIFLE (73), AKIN (74) and KDIGO (75) are three commonly used AKI grading standards. The KDIGO diagnostic standard proposed in 2012 had been reported to improve the early diagnosis of kidney injury (59,76) and to reduce the missed diagnosis rate (77), which was conducive to the early diagnosis and treatment of AKI. Our results showed that, compared with RIFLE and AKIN, the prevalence and mortality of RRT in KDIGO were relatively low. We speculate that early diagnosis and early treatment may help some burn patients with AKI avoid further deterioration of renal function, reduce the need for dialysis, and improve the prognosis of patients. Ren et al de ned AKI according to KDIGO guidelines by 48 h after admission. That prospective study reported 11.2% (11/95) AKI and only 35.4% mortality in the AKI group (64).
For burn patients with AKI, especially those with continuous deterioration of renal function, renal replacement therapy was one of the standard treatment methods. In the principle of treatment, RRT can maintain the stability of the internal environment by controlling capacity overload, reducing organ damage, clearing in ammatory mediators, and correcting electrolyte and acid-base balance disorders to bene t AKI patients. At present, only a few retrospective match historical cohort studies had found that CRRT had better prognosis than conventional non-RRT therapy (44,78). However, in a meta-analysis of the cohort studies included, we did not nd that RRT could reduce mortality. Compared with AKI or ARF, the risk of death in RRT patients was not signi cantly reduced. A metaanalysis of three RCT studies also did not show that CRRT could reduce the risk of death in burn patients with AKI compared with the standard care. You 2018 found that administration of HVHF within 3 days after admission may reduce the 90-day mortality of patients with large-area severe burns (≥ 80% TBSA) (P = 0.049). This RCT study excluded burn patients with sepsis or multiple organ failure on admission (10). Early (0-3 days after injury) burn AKI is typically due to hypovolemia, poor renal perfusion, direct cardiac suppression from TNF-alpha, and precipitation of denatured proteins (79). The therapeutic effect of renal replacement therapy in the above aetiology is better. However, late AKI is often due to sepsis, multi-organ failure, and nephrotoxic drugs (79). Thus far, it is often believed that AKI related to these aetiologies cannot reduce mortality and improve the prognosis of patients. The beginning time of CRRT was different in Liu 2016 and only lasted until 72 hours after the injury. The results showed that CRRT could not improve the prognosis of burn patients (52). Peng et al. performed an RCT study in patients with TBSA greater than 50% having sepsis. The treatment time of CRRT varied from 3 days to 8 days after burn, and the time of treatment was relatively late. There were only 10 patients each in the CRRT and control groups. The mortality rates were 10% in the CRRT group and 20% in control group, but no statistical signi cance was found (51). We speculate that early CRRT (within 3 days) may improve the prognosis of severely burned patients with early AKI. In the future, RCT studies should consider grouping burn patients with AKI according to the aetiology or time and then evaluate the therapeutic effect of RRT and its impact on the prognosis of patients. All the above three studies were from the same hospital, and the results may be biased.
Although CRRT has the advantages of stable haemodynamics and e cient clearance of in ammatory factors and metabolites, its shortcomings are that it needs systemic or regional anticoagulation. Compared with systematic anticoagulation, the risk of bleeding of regional citrate anticoagulation is smaller. The KDIGO guidelines (75) suggest the use of RCA in patients without contraindications rather than systemic heparin anticoagulation (SHA). The results of three recent RCT studies in critically ill patients showed that the RCA group had superior lter life spans and fewer adverse events than those of the SHA group (80)(81)(82). However, there was no difference in survival rate between the two groups (80,81). Cohort studies in burn patients also found that RCA had some advantages over SHA in terms of lter survival time and coagulation index. Compared with local heparin anticoagulation, RCA also has advantages in single treatment time, target rate of treatment time, coagulation index and in ammation index (70). However, anticoagulation with citric acid also has the risk of hypocalcaemia, accumulation of citric acid and aggravation of metabolic acidosis (83). Our results showed that the incidence of hypocalcaemia in the citrate group was 7.27%. Compared with the heparin group, the incidence of metabolic acidosis in the citric acid group was slightly higher, but the difference was not statistically signi cant. Regarding the side effects of RRT, the results of this study suggest that bleeding is the most common incidence of RRT in burn patients, with an incidence of approximately 11%. The advantage of citric acid in reducing bleeding may be more suitable for burn patients with AKI. Moreover, there is new evidence that RCA can safely be used in patients with liver failure (84,85) and after liver transplant (86), suggesting that local citrate anticoagulation may also be used in severe burn patients with MOF combined with renal and liver failure. Other common adverse effects of RRT include secondary infection, electrolyte disorder, thromboembolism, disequilibrium syndrome and thrombocytopenia. Compared with haemodialysis, peritoneal dialysis has some advantages in bleeding, but its risk of secondary infection is also higher. Moreover, the peritoneal dialysis catheter placement area is a common donor site or burned area (79). This limits the use of peritoneal dialysis in burn patients.
AKI in burn patients not only increases mortality (87), but also increases the risk of CKD progression and ESRD (71,72). When severe burn patients have dialysis-requiring AKI, approximately 35% of the patients need to maintain haemodialysis temporarily, even if they survive and leave the hospital. Among them, 10% of the surviving patients need haemodialysis for more than half a year. Therefore, for burn AKI or dialysis-requiring AKI survivors, it is recommended to monitor the renal function regularly within one year after discharge and to avoid the use of nephrotoxic drugs, excessive diuresis, and diarrhoea (79), to reduce the progress of CKD and to avoid the recurrence of AKI.
This systematic review has several limitations. First, there was signi cant heterogeneity in most results of RRT prevalence and mortality in this study. The clinical heterogeneity of this study may be due to the differences in the study population, RRT modalities and the end-point indicators observed in the study. The inclusion and exclusion criteria were different among different studies. There were controversies on modalities, timing, and dosage of RRT, and the standards reported in different literatures are not the same.
Outcome variables, such as mortality, also varied from study to study. Although we conducted a series of subgroup analyses on AKI diagnostic criteria, the intensive care unit and different mortality criteria, the results still showed heterogeneity. Because we were unable to obtain the original data for each patient, we cannot completely control the above confounding factors. Therefore, we used the random effect model to analyse the results. Second, we only included documents in English, Japanese and Chinese, and there may be omissions in documents reported in other languages, such as Russian. There was no literature from Russia in the studies we included. However, 58 articles and nearly 40,000 burn patients from ve continents were included in this meta-analysis, most of which were in North America, Asia, and Europe. The inclusion of a large number of literatures and patients can ensure that the results of this study were well representative, especially in North America, Asia, and Europe. Finally, this study did not analyse the starting time of RRT for burn patients with AKI. At present, the timing of RRT for critically ill patients is still controversial. At the beginning of this study, we plan to analyse the timing of RRT in burn patients. However, even if 58 articles were included, there is still a lack of head-to-head study on the starting time of RRT for burn patients with AKI. There was only one cohort study that was divided into groups according to the AKI level of patients at the beginning of CRRT. The early CRRT group was de ned according to the patients who started CRRT at the risk stage of the RIFLE criteria. The results showed there were no signi cant differences in mortality by the severity of AKI at the time of CRRT initiation (11). We suggest that more head-to-head cohort studies or RCT studies can be designed in the future regarding the timing of RRT in burn patients.
Our meta-analysis had a number of strengths. In this study, 58 articles from 1979 to 2019 were included, involving nearly 40,000 burn patients. It has obvious representative advantages for the prevalence and mortality of RRT for burn patients with high statistical variability. Second, we analysed comprehensively and systematically whether RRT can improve the prognosis (mainly mortality) of burn patients and performed a subgroup analysis from different anticoagulation methods, RRT-related adverse reactions and renal outcome. There is certain value in designing RRT schemes for severe burn patients with AKI in the future.

Conclusions:
The prevalence of RRT is not low; approximately, one-third of burn patients with AKI need RRT. The mortality of burn patients with RRT is very high and accounts for 1/3 of the total deaths. There is no evidence that RRT can improve the prognosis of burn patients with AKI. Regional citrate anticoagulation has some advantages in reducing bleeding and extending lter life spans, which may be more suitable for severe burn patients with CRRT. Declarations: Authors' contributions C.GY and L.JJ contributed to the conception and design of the study. D.ZY and C.FK selected the studies and extracted the data. D.ZY evaluated the study quality. D.ZY and C.FK performed the statistical analyses and data presentation. The manuscript was drafted by D.ZY, with assistance by C.FK and L.JJ, and the manuscript was critically revised by C.XM and C.GY All authors have read and approved the nal manuscript.  Flow diagram of the study selection process.

Figure 2
Risk ratios for mortality of burn patients with AKI, ARF, and RRT in cohort studies.

Figure 3
Risk ratio for mortality of burned patients with CRRT in RCT studies.